1-25563697-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015627.3(LDLRAP1):c.653C>T(p.Thr218Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,904 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. T218M) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0076 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 18 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6

Conservation

PhyloP100: 0.336

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:

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=0.0025242567).

BP6

Variant 1-25563697-C-T is Benign according to our data. Variant chr1-25563697-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520395.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr1-25563697-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00758 (1154/152338) while in subpopulation AFR AF= 0.026 (1079/41574). AF 95% confidence interval is 0.0247. There are 12 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLRAP1	NM_015627.3 link	c.653C>T	p.Thr218Ile	missense_variant	Exon 7 of 9	ENST00000374338.5	NP_056442.2	Q5SW96B3KR97

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LDLRAP1	ENST00000374338.5 link	c.653C>T	p.Thr218Ile	missense_variant	Exon 7 of 9	1	NM_015627.3	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000484476.5 link	n.375C>T		non_coding_transcript_exon_variant	Exon 2 of 4	1
LDLRAP1	ENST00000474283.1 link	n.64C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3
LDLRAP1	ENST00000488127.1 link	n.1123C>T		non_coding_transcript_exon_variant	Exon 6 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.00754

AC:

1147

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00217

AC:

545

AN:

250890

Hom.:

AF XY:

0.00155

AC XY:

211

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.0283

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000859

AC:

1256

AN:

1461566

Hom.:

Cov.:

AF XY:

0.000737

AC XY:

536

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.0289

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000755

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00758

AC:

1154

AN:

152338

Hom.:

Cov.:

AF XY:

0.00658

AC XY:

490

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0260

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00914

ESP6500AA

AF:

0.0220

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00271

AC:

329

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 4

Pathogenic:1Uncertain:1Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

NM_015627.2:c.653C>T in the LDLRAP1 gene has an allele frequency of 0.028 in African subpopulation in the gnomAD database, including 13 homozygous occurrences. It was detected in one individual with autosomal recessive hypercholesterolemia, compound heterozygous with c.863C>T (p.Ser288Leu) (PMID: 29245109). Benign computational verdict because benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2, BP4, PM3. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jun 19, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:2

Oct 08, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2020

H3Africa Consortium

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.08, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Familial hypercholesterolemia

Benign:1

Jan 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.4

DANN

Benign

0.91

DEOGEN2

Benign

0.29

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.6

REVEL

Benign

0.034

Sift

Benign

0.40

Sift4G

Benign

0.45

Polyphen

0.045

Vest4

0.13

MVP

0.53

MPC

0.21

ClinPred

0.0044

GERP RS

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.072

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