chr1-25543763-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLRAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
LDLRAP1	NM_015627.3 link	c.65G>T	p.Trp22Leu	missense_variant	Exon 1 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.65G>T	p.Trp22Leu	missense_variant	Exon 1 of 9	1	NM_015627.3	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000718277.1 link	c.65G>T	p.Trp22Leu	missense_variant	Exon 1 of 10			ENSP00000520715.1
LDLRAP1	ENST00000718287.1 link	c.65G>T	p.Trp22Leu	missense_variant	Exon 1 of 6			ENSP00000520725.1
LDLRAP1	ENST00000718288.1 link	n.65G>T		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000520726.1

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

African (AFR)

AF:

0.0000455

AC:

AN:

22000

American (AMR)

AF:

0.000131

AC:

AN:

7620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13142

East Asian (EAS)

AF:

0.00

AC:

AN:

24532

South Asian (SAS)

AF:

0.00

AC:

AN:

19358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2854

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

904862

Other (OTH)

AF:

0.0000239

AC:

AN:

41846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151672

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74100

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41382

American (AMR)

AF:

0.0000657

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67852

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Mar 18, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

3.2

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

PromoterAI

0.048

Neutral

(source)

Varity_R

0.40

gMVP

0.38

Mutation Taster

=33/67

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr1-25543763-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over