rs41291058

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_015627.3(LDLRAP1):c.712C>T(p.Arg238Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,613,906 control chromosomes in the GnomAD database, including 1,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R238Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 112 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1633 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -0.248

Publications

14 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032408237).

BP6

Variant 1-25563756-C-T is Benign according to our data. Variant chr1-25563756-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296986.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

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.712C>T	p.Arg238Trp	missense	Exon 7 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.712C>T	p.Arg238Trp	missense	Exon 7 of 9	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000484476.5	TSL:1	n.434C>T		non_coding_transcript_exon	Exon 2 of 4
LDLRAP1	ENST00000894925.1		c.775C>T	p.Arg259Trp	missense	Exon 8 of 10	ENSP00000564984.1

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4830

AN:

152208

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00946

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0253

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0406

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0499

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0334

AC:

8370

AN:

250582

AF XY:

0.0341

show subpopulations

Gnomad AFR exome

AF:

0.00842

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0251

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0435

Gnomad NFE exome

AF:

0.0529

Gnomad OTH exome

AF:

0.0402

GnomAD4 exome

AF:

0.0431

AC:

63049

AN:

1461580

Hom.:

1633

Cov.:

AF XY:

0.0422

AC XY:

30701

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00708

AC:

237

AN:

33480

American (AMR)

AF:

0.0200

AC:

894

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

640

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00610

AC:

526

AN:

86258

European-Finnish (FIN)

AF:

0.0407

AC:

2164

AN:

53152

Middle Eastern (MID)

AF:

0.0251

AC:

145

AN:

5766

European-Non Finnish (NFE)

AF:

0.0506

AC:

56218

AN:

1111968

Other (OTH)

AF:

0.0368

AC:

2221

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

3282

6563

9845

13126

16408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2046

4092

6138

8184

10230

<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:

0.0317

AC:

4827

AN:

152326

Hom.:

112

Cov.:

AF XY:

0.0294

AC XY:

2188

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00943

AC:

392

AN:

41580

American (AMR)

AF:

0.0252

AC:

386

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00331

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0406

AC:

431

AN:

10622

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0499

AC:

3391

AN:

68012

Other (OTH)

AF:

0.0298

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

233

465

698

930

1163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0349

Hom.:

Bravo

AF:

0.0301

TwinsUK

AF:

0.0550

AC:

204

ALSPAC

AF:

0.0537

AC:

207

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0497

AC:

427

ExAC

AF:

0.0355

AC:

4307

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0491

EpiControl

AF:

0.0501

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 4 (5)

not specified (4)

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

PhyloP100

-0.25

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.11

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.14

MPC

0.21

ClinPred

0.031

GERP RS

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.14

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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