Genetic Variant NM_015627.3:c.6C>A (chr1-25543704-C-A) – 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.6C>A(p.Asp2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000094 in 1,063,554 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D2D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.4e-7 ( 0 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.818

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:

Genome browser will be placed here

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.6C>A	p.Asp2Glu	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.6C>A	p.Asp2Glu	missense	Exon 1 of 9	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000894925.1		c.6C>A	p.Asp2Glu	missense	Exon 1 of 10	ENSP00000564984.1
LDLRAP1	ENST00000894924.1		c.6C>A	p.Asp2Glu	missense	Exon 1 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.40e-7

AC:

AN:

1063554

Hom.:

Cov.:

AF XY:

0.00000199

AC XY:

AN XY:

503094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22138

American (AMR)

AF:

0.00

AC:

AN:

7742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13264

East Asian (EAS)

AF:

0.00

AC:

AN:

25030

South Asian (SAS)

AF:

0.00

AC:

AN:

19552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3146

European-Non Finnish (NFE)

AF:

0.00000110

AC:

AN:

909736

Other (OTH)

AF:

0.00

AC:

AN:

42162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

0.17

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.94

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.8

PhyloP100

0.82

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.4

REVEL

Benign

0.12

Sift

Benign

0.057

Sift4G

Benign

0.11

Polyphen

0.98

Vest4

0.071

MutPred

0.25

Loss of helix (P = 0.079)

MVP

0.72

MPC

0.19

ClinPred

0.87

GERP RS

4.0

PromoterAI

-0.096

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.45

Mutation Taster

=82/18

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over