chr12-124814996-C-T

Position:

• chr12-124814996-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 33)
  • Exomes 𝑓: 0.012 (224 hom.)
• Consequence: SCARB1 NM_005505.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 1248125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-124814996-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCARB1	NM_005505.5	c.403G>A	p.Val135Ile	missense_variant	3/13	ENST00000261693.11	NP_005496.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB1	ENST00000261693.11	c.403G>A	p.Val135Ile	missense_variant	3/13	1	NM_005505.5	ENSP00000261693.6

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1752 AN: 152148 Hom.: 20 Cov.: 33

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

GnomAD3 exomes AF: 0.0124 AC: 3110 AN: 251294 Hom.: 54 AF XY: 0.0143 AC XY: 1944 AN XY: 135852

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 SAS exome AF: 0.0416

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.: 32 AF XY: 0.0133 AC XY: 9657 AN XY: 727220

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0420

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0115 AC: 1749 AN: 152266 Hom.: 20 Cov.: 33 AF XY: 0.0119 AC XY: 884 AN XY: 74448

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0410

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0118 Hom.: 22

Bravo AF: 0.0110

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00988 AC: 85

ExAC AF: 0.0132 AC: 1603

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0144

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2020	This variant is associated with the following publications: (PMID: 29596577, 25245032, 26571379, 17476110, 24503134) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.081	.;T;.;T;T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
MetaRNN	Benign	0.0031	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.84	L;L;L;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.63	N;N;N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.58	T;T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.32, 0.046, 0.056	.;B;B;B;.;.
Vest4		0.023
MPC		0.38
ClinPred		0.0064	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs5891; hg19: chr12-125299542;