Genetic Variant NM_005505.5:c.403G>A (chr12-124814996-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005505.5(SCARB1):c.403G>A(p.Val135Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,104 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 20 hom., cov: 33)

Exomes 𝑓: 0.012 ( 224 hom. )

Consequence

SCARB1
NM_005505.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.16

Publications

41 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031484663).

BP6

Variant 12-124814996-C-T is Benign according to our data. Variant chr12-124814996-C-T is described in ClinVar as Benign. ClinVar VariationId is 1248125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0115 (1749/152266) while in subpopulation SAS AF = 0.041 (198/4824). AF 95% confidence interval is 0.0364. There are 20 homozygotes in GnomAd4. There are 884 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005505.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCARB1	NM_005505.5	MANE Select	c.403G>A	p.Val135Ile	missense	Exon 3 of 13	NP_005496.4
SCARB1	NM_001367981.1		c.403G>A	p.Val135Ile	missense	Exon 3 of 12	NP_001354910.1	Q8WTV0-1
SCARB1	NM_001367982.1		c.280G>A	p.Val94Ile	missense	Exon 3 of 11	NP_001354911.1	B3KW46

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCARB1	ENST00000261693.11	TSL:1 MANE Select	c.403G>A	p.Val135Ile	missense	Exon 3 of 13	ENSP00000261693.6	Q8WTV0-2
SCARB1	ENST00000546215.5	TSL:1	c.403G>A	p.Val135Ile	missense	Exon 3 of 13	ENSP00000442862.1	B7ZKQ9
SCARB1	ENST00000535005.5	TSL:1	n.718G>A		non_coding_transcript_exon	Exon 4 of 13

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1752

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0412

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0124

AC:

3110

AN:

251294

AF XY:

0.0143

show subpopulations

Gnomad AFR exome

AF:

0.0136

Gnomad AMR exome

AF:

0.00500

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0123

AC:

18003

AN:

1461838

Hom.:

224

Cov.:

AF XY:

0.0133

AC XY:

9657

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0139

AC:

466

AN:

33478

American (AMR)

AF:

0.00561

AC:

251

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00853

AC:

223

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0420

AC:

3622

AN:

86252

European-Finnish (FIN)

AF:

0.00197

AC:

105

AN:

53402

Middle Eastern (MID)

AF:

0.0255

AC:

147

AN:

5768

European-Non Finnish (NFE)

AF:

0.0112

AC:

12460

AN:

1111992

Other (OTH)

AF:

0.0120

AC:

724

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1135

2269

3404

4538

5673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.0115

AC:

1749

AN:

152266

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

884

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0140

AC:

583

AN:

41554

American (AMR)

AF:

0.00706

AC:

108

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0410

AC:

198

AN:

4824

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

760

AN:

68022

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0117

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00988

AC:

ExAC

AF:

0.0132

AC:

1603

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0144

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.081

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.84

PhyloP100

1.2

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.63

REVEL

Benign

0.079

Sift

Benign

0.58

Sift4G

Benign

0.21

Polyphen

0.32

Vest4

0.023

MPC

0.38

ClinPred

0.0064

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.62

Mutation Taster

=99/1

polymorphism (auto)

(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