12-20815749-A-G

Variant summary

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

The NM_019844.4(SLCO1B3):c.11A>G(p.His4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,590,812 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.231

Genes affected

SLCO1B3 (HGNC:10961): (solute carrier organic anion transporter family member 1B3) This gene encodes a liver-specific member of the organic anion transporter family. The encoded protein is a transmembrane receptor that mediates the sodium-independent uptake of endogenous and xenobiotic compounds and plays a critical role in bile acid and bilirubin transport. Mutations in this gene are a cause of Rotor type hyperbilirubinemia. Alternative splicing of this gene and the use of alternative promoters results in transcript variants encoding different isoforms that differ in their tissue specificity. [provided by RefSeq, Mar 2017]

SLCO1B3-SLCO1B7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028271973).
• BP6: Variant 12-20815749-A-G is Benign according to our data. Variant chr12-20815749-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 376892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0067 (1021/152334) while in subpopulation AFR AF= 0.0237 (987/41582). AF 95% confidence interval is 0.0225. There are 13 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLCO1B3	NM_019844.4	c.11A>G	p.His4Arg	missense_variant	3/16	ENST00000381545.8
SLCO1B3-SLCO1B7	NM_001371097.1	c.11A>G	p.His4Arg	missense_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.11A>G	p.His4Arg	missense_variant	3/16	2	NM_019844.4	P1
SLCO1B3	ENST00000261196.6	c.11A>G	p.His4Arg	missense_variant	1/14	1		P1
SLCO1B3	ENST00000540853.5	c.11A>G	p.His4Arg	missense_variant	2/8	1

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1001 AN: 152216 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00166 AC: 393 AN: 237418 Hom.: 6 AF XY: 0.00118 AC XY: 152 AN XY: 128914

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.000964

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000932

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.000636 AC: 915 AN: 1438478 Hom.: 12 Cov.: 28 AF XY: 0.000534 AC XY: 382 AN XY: 715812

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.000920

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000192

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000547

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.00670 AC: 1021 AN: 152334 Hom.: 13 Cov.: 33 AF XY: 0.00664 AC XY: 495 AN XY: 74506

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00707

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00202 AC: 7 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 14, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Oct 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	4.6
Dann	Benign	0.51
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.52	T;.;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.48	N;N;N;N;N
REVEL	Benign	0.010
Sift	Benign	0.26	T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.17	.;B;B;.;.
Vest4		0.076, 0.17, 0.097
MVP		0.13
MPC		0.0067, 0.0086
ClinPred		0.0046	T
GERP RS		-0.77
Varity_R		0.033
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61612406; hg19: chr12-20968683; COSMIC: COSV104370096;