chr1-25563756-C-T

Position:

chr1-25563756-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_015627.3(LDLRAP1):c.712C>T(p.Arg238Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,613,906 control chromosomes in the GnomAD database, including 1,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 112 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1633 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: -0.248

Variant links:

Genes affected

LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]

LDLRAP1 links:

LDLRAP1 (HGNC:):

LDLRAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032408237).

BP6

Variant 1-25563756-C-T is Benign according to our data. Variant chr1-25563756-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296986.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=7}. Variant chr1-25563756-C-T is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLRAP1	NM_015627.3 linkuse as main transcript	c.712C>T	p.Arg238Trp	missense_variant	7/9	ENST00000374338.5	NP_056442.2	Q5SW96B3KR97

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LDLRAP1	ENST00000374338.5 linkuse as main transcript	c.712C>T	p.Arg238Trp	missense_variant	7/9	1	NM_015627.3	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000484476.5 linkuse as main transcript	n.434C>T		non_coding_transcript_exon_variant	2/4	1
LDLRAP1	ENST00000474283.1 linkuse as main transcript	n.123C>T		non_coding_transcript_exon_variant	1/3	3
LDLRAP1	ENST00000488127.1 linkuse as main transcript	n.1182C>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4830

AN:

152208

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00946

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0253

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0406

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0499

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0334

AC:

8370

AN:

250582

Hom.:

196

AF XY:

0.0341

AC XY:

4621

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.00842

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0251

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00555

Gnomad FIN exome

AF:

0.0435

Gnomad NFE exome

AF:

0.0529

Gnomad OTH exome

AF:

0.0402

GnomAD4 exome

AF:

0.0431

AC:

63049

AN:

1461580

Hom.:

1633

Cov.:

AF XY:

0.0422

AC XY:

30701

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00708

Gnomad4 AMR exome

AF:

0.0200

Gnomad4 ASJ exome

AF:

0.0245

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00610

Gnomad4 FIN exome

AF:

0.0407

Gnomad4 NFE exome

AF:

0.0506

Gnomad4 OTH exome

AF:

0.0368

GnomAD4 genome

AF:

0.0317

AC:

4827

AN:

152326

Hom.:

112

Cov.:

AF XY:

0.0294

AC XY:

2188

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00943

Gnomad4 AMR

AF:

0.0252

Gnomad4 ASJ

AF:

0.0233

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.0406

Gnomad4 NFE

AF:

0.0499

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0389

Hom.:

Bravo

AF:

0.0301

TwinsUK

AF:

0.0550

AC:

204

ALSPAC

AF:

0.0537

AC:

207

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0497

AC:

427

ExAC

AF:

0.0355

AC:

4307

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0491

EpiControl

AF:

0.0501

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 4

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 30, 2022	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 472/13006=3.6% -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 02, 2017

Variant summary: The LDLRAP1 c.712C>T (p.Arg238Trp) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4281/120134 control chromosomes (112 homozygotes) at a frequency of 0.0356352, which is approximately 45 times the estimated maximal expected allele frequency of a pathogenic LDLRAP1 variant (0.0007906), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.11

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.14

MPC

0.21

ClinPred

0.031

GERP RS

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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