rs74830677

Positions:

chr12-124800125-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_005505.5(SCARB1):c.1127C>T(p.Pro376Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 1,609,304 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 14 hom. )

Consequence

SCARB1
NM_005505.5 missense, splice_region

Scores

Splicing: ADA: 0.9876

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:1O:1

Conservation

PhyloP100: 8.75

Variant links:

Genes affected

SCARB1 (HGNC:1664): (scavenger receptor class B member 1) The protein encoded by this gene is a plasma membrane receptor for high density lipoprotein cholesterol (HDL). The encoded protein mediates cholesterol transfer to and from HDL. In addition, this protein is a receptor for hepatitis C virus glycoprotein E2 and facilitates cell entry by the virus, SARS-CoV2. [provided by RefSeq, Oct 2021]

SCARB1 links:

ENSG00000287242 (HGNC:):

ENSG00000287242 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCARB1	NM_005505.5 link	c.1127C>T	p.Pro376Leu	missense_variant, splice_region_variant	8/13	ENST00000261693.11	NP_005496.4	Q8WTV0-2A0A024RBS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB1	ENST00000261693.11 link	c.1127C>T	p.Pro376Leu	missense_variant, splice_region_variant	8/13	1	NM_005505.5	ENSP00000261693.6		Q8WTV0-2

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000991

AC:

249

AN:

251294

Hom.:

AF XY:

0.000928

AC XY:

126

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000525

AC:

765

AN:

1457106

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

382

AN XY:

725224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0203

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152198

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0256

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000627

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000651

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 6

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 22, 2019	This variant has been previously reported as a heterozygous or homozygous change in patients with high HDL cholesterol and coronary heart disease risk (PMID: 26965621). In vitro and in vivo studies show that in the heterozygous state this variant causes a profound reduction in HDL uptake (PMID: 26965621). This variant is present in the heterozygous state in the gnomAD population database at a frequency of .09% (254/277086) and thus is presumed to be rare. However, it is more common in some ethnic groups, reaching allele frequencies of 2%. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.1127C>T (p.Pro376Leu) variant is classified as pathogenic . -
association, no assertion criteria provided	literature only	OMIM	Jul 20, 2018	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;D;.;T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.076

T;T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.7

H;H;H;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-9.3

D;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.060

T;T;D;D;T

Polyphen

0.86, 0.83, 0.69

.;P;P;P;.

Vest4

0.99

MVP

0.91

MPC

0.78

ClinPred

0.69

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over