rs121908326

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_015627.3(LDLRAP1):c.605C>A(p.Ser202Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 1,613,942 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. S202H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 6 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:2

Conservation

PhyloP100: 0.592

Publications

11 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15271023).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00165 (251/152254) while in subpopulation AFR AF = 0.00318 (132/41560). AF 95% confidence interval is 0.00274. There are 0 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

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.605C>A	p.Ser202Tyr	missense	Exon 6 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.605C>A	p.Ser202Tyr	missense	Exon 6 of 9	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000484476.5	TSL:1	n.327C>A		non_coding_transcript_exon	Exon 1 of 4
LDLRAP1	ENST00000894925.1		c.668C>A	p.Ser223Tyr	missense	Exon 7 of 10	ENSP00000564984.1

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00115

AC:

289

AN:

250500

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.00267

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00289

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.000755

AC:

1103

AN:

1461688

Hom.:

Cov.:

AF XY:

0.000822

AC XY:

598

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00299

AC:

100

AN:

33476

American (AMR)

AF:

0.00228

AC:

102

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000626

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000542

AC:

603

AN:

1111868

Other (OTH)

AF:

0.00174

AC:

105

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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

AF:

0.00165

AC:

251

AN:

152254

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41560

American (AMR)

AF:

0.00229

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

67998

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00186

ExAC

AF:

0.00116

AC:

141

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00214

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 4 (6)

Familial hypercholesterolemia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.56

M_CAP

Benign

0.080

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.1

PhyloP100

0.59

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.098

Sift

Uncertain

0.010

Sift4G

Uncertain

0.019

Polyphen

0.97

Vest4

0.36

MVP

0.71

MPC

0.42

ClinPred

0.019

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.079

gMVP

0.32

Mutation Taster

=87/13

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over