Genetic Variant LDLRAP1:p.Leu4Phe (chr1-25543708-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015627.3(LDLRAP1):c.10C>T(p.Leu4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015627.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLRAP1	NM_015627.3	MANE Select	c.10C>T	p.Leu4Phe	missense	Exon 1 of 9	NP_056442.2	Q5SW96

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLRAP1	ENST00000374338.5	TSL:1 MANE Select	c.10C>T	p.Leu4Phe	missense	Exon 1 of 9	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000894925.1		c.10C>T	p.Leu4Phe	missense	Exon 1 of 10	ENSP00000564984.1
LDLRAP1	ENST00000894924.1		c.10C>T	p.Leu4Phe	missense	Exon 1 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1063354

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

502850

African (AFR)

AF:

0.00

AC:

AN:

22146

American (AMR)

AF:

0.00

AC:

AN:

7740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13268

East Asian (EAS)

AF:

0.00

AC:

AN:

25026

South Asian (SAS)

AF:

0.00

AC:

AN:

19546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3152

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

909540

Other (OTH)

AF:

0.00

AC:

AN:

42166

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.3

PhyloP100

2.2

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.9

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.31

MutPred

0.26

Loss of stability (P = 0.1104)

MVP

0.77

MPC

0.79

ClinPred

0.97

GERP RS

4.0

PromoterAI

0.027

Neutral

(source)

Varity_R

0.56

gMVP

0.62

Mutation Taster

=60/40

polymorphism

(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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over