19-11120436-C-T

Position:

chr19-11120436-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000558518.6(LDLR):c.2054C>T(p.Pro685Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P685R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35O:1

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript ENST00000558518.6 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000558518.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11120436-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2713547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 19-11120436-C-T is Pathogenic according to our data. Variant chr19-11120436-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120436-C-T is described in Lovd as [Pathogenic]. Variant chr19-11120436-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2054C>T	p.Pro685Leu	missense_variant	14/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2054C>T	p.Pro685Leu	missense_variant	14/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251236

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000168

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:18

Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 29, 2024	This missense variant replaces proline with leucine at codon 685 of the EGF-like repeat C in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro664Leu in the mature protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional assays have demonstrated that the variant protein shows defective processing, accelerated turnover, reduced cell surface expression and impaired LDLR activity (PMID: 1464748, 25647241, 2920733, 3816797). This variant has been reported in over 200 individuals affected with familial hypercholesterolemia (PMID: 7583548, 9763532, 1464748, 1493640, 15199436, 1884514, 19318025, 19446849, 20828696, 21310417, 21382890, 22390909, 23375686, 23680767, 26343872, 26892515, 33740630, 34456200, 35052492, 36422519). It has been shown that this variant segregates with disease in multiple affected individuals across two large families (PMID: 1493640, 1830890, 2726768). This variant has been identified in 9/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Pro685Ser, is considered to be disease-causing (ClinVar variation ID: 252194), suggesting that proline at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/200 non-FH alleles -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Apr 13, 2010	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM3+PS4+PP1_Strong+PS3_Supporting -

not provided

Pathogenic:8Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant disrupts LDL receptor activity and inhibits LDL-uptake in cells (King-Underwood et al., 1991; Rubinsztein et al., 1992; Tada et al., 2009; Thormaehlen et al., 2015); Also known as P664L and FH Gujerat/Frosinone-1/Kanazawa-2; This variant is associated with the following publications: (PMID: 17142622, 19446849, 11031227, 30592178, 31447099, 1884514, 7583548, 2726768, 1830890, 1464748, 1493640, 9254862, 9763532, 17347910, 20828696, 21382890, 21310417, 22390909, 23155708, 23680767, 24529145, 25647241, 25487149, 26892515, 27831900, 24507775, 28965616, 30526649, 30112042, 30971288, 19013141, 23669246, 31491741, 34040191, 34570182, 32977124, 32041611, 32770674, 32331935, 33740630, 34037665, 33087929, 27535533, 26582918, 23375686) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 23, 2020	This variant has been reported in individuals affected with homozygous or heterozygous familial hypercholesterolemia in the published literature (PMID: 26892515 (2016), 26343872 (2015), 22698793 (2012), 18718593 (2009), 12417285 (2002), 9763532 (1998), 1830890 (1991), 2726768 (1989)). Additionally, functional studies indicate that this variant is damaging to LDL receptor function (PMID: 25647241 (2015), 19013141 (2009), 18718593 (2009)). This variant has also been reported to segregate with hypercholesterolemia in multiple families (PMID: 23155708 (2012), 18718593 (2009), 2726768 (1989)). Therefore, the variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LDLR: PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	PP1_strong, PP3, PP4, PM1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2022	The LDLR c.2054C>T; p.Pro685Leu variant (rs28942084), also known as P664L, is reported in numerous individuals affected with homozygous or heterozygous familial hypercholesterolemia, and shown to segregate with hypercholesterolemia in multiple families (Cheng 2018, Lee 2019, Miyake 2009, Pandey 2016, Sharifi 2016, Soutar 1989, Sturm 2021). This variant is also reported in ClinVar (Variation ID: 3702). Furthermore, functional analyses demonstrate an affect of this variant on protein function (Rubinsztein 1992, Tada 2009, Thormaehlen 2015). This variant is found in the general population with an overall allele frequency of 0.003% (9/282638 alleles) in the Genome Aggregation Database. The proline at codon 685 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.883). Based on available information, this variant is considered to be pathogenic. References: Cheng X et al. Novel compound heterozygous mutations in low density lipoprotein receptor gene causes a severe phenotype in a Chinese hypercholesterolemia family. Exp Ther Med. 2018 Aug;16(2):901-907. PMID: 30112042. Lee C et al. Effects of familial hypercholesterolemia-associated genes on the phenotype of premature myocardial infarction. Lipids Health Dis. 2019 Apr 11;18(1):95. PMID: 30971288. Miyake Y et al. Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. Atherosclerosis. 2009 Mar;203(1):153-60. PMID: 18718593. Pandey S et al. Cascade Screening for Familial Hypercholesterolemia: PCR Methods with Melting-Curve Genotyping for the Targeted Molecular Detection of Apolipoprotein B and LDL Receptor Gene Mutations to Identify Affected Relatives. J Appl Lab Med. 2016 Sep 1;1(2):109-118. PMID: 33626794. Rubinsztein DC et al. Identification and properties of the proline664-leucine mutant LDL receptor in South Africans of Indian origin. J Lipid Res. 1992 Nov;33(11):1647-55. PMID: 1464748. Sharifi M et al. The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. Metabolism. 2016 Mar;65(3):48-53. PMID: 26892515. Soutar AK et al. Identification of a point mutation in growth factor repeat C of the low density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia that affects ligand binding and intracellular movement of receptors. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4166-70. PMID: 2726768. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. Tada H et al. A novel method for determining functional LDL receptor activity in familial hypercholesterolemia: application of the CD3/CD28 assay in lymphocytes. Clin Chim Acta. 2009 Feb;400(1-2):42-7. PMID: 19013141. Thormaehlen AS et al. Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. PLoS Genet. 2015 Feb 3;11(2):e1004855. PMID: 25647241. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Familial hypercholesterolemia

Pathogenic:6

Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2020	Variant summary: LDLR c.2054C>T (p.Pro685Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251236 control chromosomes. c.2054C>T has been extensively reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Tichy_2012, Bertolini_2013, Soutar_1989, Futema_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on LDL-receptor activity (example, Bertolini_2013, Bertolini_1999, Knight_1989). The most pronounced variant effect results in 10%-<30% of normal activity. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=9)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 685 of the LDLR protein (p.Pro685Leu). This variant is present in population databases (rs28942084, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2726768, 11031227, 12124988, 15359125, 18718593, 21382890, 23155708, 23375686, 23669246). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Pro664Leu. ClinVar contains an entry for this variant (Variation ID: 3702). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 19013141). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 12, 2023	This missense variant replaces proline with leucine at codon 685 of the EGF-like repeat C in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro664Leu in the mature protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional assays have demonstrated that the variant protein shows defective processing, accelerated turnover, reduced cell surface expression and impaired LDLR activity (PMID: 1464748, 25647241, 2920733, 3816797). This variant has been reported in over 200 individuals affected with familial hypercholesterolemia (PMID: 7583548, 9763532, 1464748, 1493640, 15199436, 1884514, 19318025, 19446849, 20828696, 21310417, 21382890, 22390909, 23375686, 23680767, 26343872, 26892515, 33740630, 34456200, 35052492, 36422519). It has been shown that this variant segregates with disease in multiple affected individuals across two large families (PMID: 1493640, 1830890, 2726768). This variant has been identified in 9/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Pro685Ser, is considered to be disease-causing (ClinVar variation ID: 252194), suggesting that proline at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 27, 2021	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2015

The p.Pro685Leu variant in LDLR, also described as p.Pro664Leu in the literature , has been reported in >40 individuals with familial hypercholesterolemia (FH), segregated with disease in >40 affected relatives from at least 4 families, and was identified in the homozygous state in at least 10 individuals with FH (Berto lini 2013, Sharifi 2016, Medeiros 2010,Rubinsztein 1992, Soutar 1989, Soutar 199 1, Thormaehlen 2015, Van Der Graaf 2011). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID 3702) and was identified i n 6/126656 European chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs28942084). However, this frequency is low enough to be consistent with the frequency of FH in the general population. In v itro functional studies provide some evidence that the p.Pro685Leu variant may i mpact protein function (Knight 1989, Rubinsztein 1992, Thormaehlen 2015). In sum mary, this variant meets criteria to be classified as pathogenic for familial hy percholesterolemia in an autosomal dominant manner based upon presence in multip le affected individuals, segregation studies, low frequency in controls and func tional evidence. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting . -

LDLR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2024

The LDLR c.2054C>T variant is predicted to result in the amino acid substitution p.Pro685Leu. This variant has been repeatedly reported to be causative for hypercholesterolemia (see for example at Bertolini et al. 2013. PubMed ID: 23375686; Hori et al. 2019. PubMed ID: 31491741; Gratton et al. 2023. PubMed ID: 37409534). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3702/). This variant is interpreted as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

The c.2054C>T (p.P685L) alteration is located in exon 14 (coding exon 14) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 2054, causing the proline (P) at amino acid position 685 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (9/282638) total alleles studied. The highest observed frequency was 0.012% (3/24966) of African alleles. This alteration (also referred to as p.P664L) has been described in multiple individuals with familial hypercholesterolemia from varying ethnic backgrounds, including homozygous and compound heterozygous cases, and has been reported to segregate with disease in several families (Soutar, 1989; King-Underwood, 1991; Defesche, 1992; Maruyama, 1995; Mak, 1998; Leren, 2004; Alonso, 2009; Guardamagna, 2009; Medeiros, 2010; Shin, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration has been reported to result in defective LDLR activity in studies of patient derived cells (Knight, 1989; King-Underwood, 1991; Tada, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-9.4

D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.87

MVP

1.0

MPC

0.82

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over