Genetic Variant SCARB1:p.Pro376Arg (chr12-124800125-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005505.5(SCARB1):c.1127C>G(p.Pro376Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P376L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SCARB1
NM_005505.5 missense, splice_region

Scores

Splicing: ADA: 0.9707

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.75

Publications

0 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:

ENSG00000287242 (HGNC:):

ENSG00000287242 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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
SCARB1	NM_005505.5	MANE Select	c.1127C>G	p.Pro376Arg	missense splice_region	Exon 8 of 13	NP_005496.4
SCARB1	NM_001367981.1		c.1127C>G	p.Pro376Arg	missense splice_region	Exon 8 of 12	NP_001354910.1
SCARB1	NM_001367982.1		c.1004C>G	p.Pro335Arg	missense splice_region	Exon 8 of 11	NP_001354911.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCARB1	ENST00000261693.11	TSL:1 MANE Select	c.1127C>G	p.Pro376Arg	missense splice_region	Exon 8 of 13	ENSP00000261693.6
SCARB1	ENST00000546215.5	TSL:1	c.1127C>G	p.Pro376Arg	missense splice_region	Exon 8 of 13	ENSP00000442862.1
SCARB1	ENST00000535005.5	TSL:1	n.1442C>G		splice_region non_coding_transcript_exon	Exon 9 of 13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33342

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107852

Other (OTH)

AF:

0.00

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.7

PhyloP100

8.7

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-8.1

REVEL

Pathogenic

0.85

Sift

Benign

0.071

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.98

MutPred

0.91

Gain of solvent accessibility (P = 0.0584)

MVP

0.95

MPC

1.2

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.97

Mutation Taster

=19/81

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.75

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over