Variant 1-25543763-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015627.3(LDLRAP1):c.65G>T(p.Trp22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,208,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W22R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.24

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40298992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLRAP1	NM_015627.3 linkuse as main transcript	c.65G>T	p.Trp22Leu	missense_variant	1/9	ENST00000374338.5	NP_056442.2	Q5SW96B3KR97

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLRAP1	ENST00000374338.5 linkuse as main transcript	c.65G>T	p.Trp22Leu	missense_variant	1/9	1	NM_015627.3	ENSP00000363458.4		Q5SW96

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1056876

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

498900

show subpopulations

Gnomad4 AFR exome

AF:

0.0000455

Gnomad4 AMR exome

AF:

0.000131

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.0000239

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151672

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74100

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 4

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 08, 2022	This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 22 of the LDLRAP1 protein (p.Trp22Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLRAP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Uncertain

0.73

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.1

REVEL

Benign

0.13

Sift

Benign

0.049

Sift4G

Benign

0.12

Polyphen

0.48

Vest4

0.33

MutPred

0.41

Loss of MoRF binding (P = 0.0567);

MVP

0.50

MPC

0.35

ClinPred

0.79

GERP RS

3.0

Varity_R

0.40

gMVP

0.38

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