NM_019844.4:c.767G>C

Variant names:

• chr12-20875274-G-C
• rs60140950
• NM_019844.4:c.767G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The NM_019844.4(SLCO1B3):​c.767G>C​(p.Gly256Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,612,444 control chromosomes in the GnomAD database, including 16,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1132 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14884 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.83
• Publications: 36 publications found

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:54403): (SLCO1B3-SLCO1B7 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring SLCO1B3 (solute carrier organic anion transporter family member 1B3) and SLCO1B7 (solute carrier organic anion transporter family member 1B7 (putative)) genes on chromosome 12. The readthrough transcript encodes a protein that shares sequence identity with both the upstream and downstream genes. [provided by RefSeq, Jun 2019]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.003154099).
• BP6: Variant 12-20875274-G-C is Benign according to our data. Variant chr12-20875274-G-C is described in ClinVar as Benign. ClinVar VariationId is 307896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	NM_019844.4	MANE Select	c.767G>C	p.Gly256Ala	missense	Exon 9 of 16	NP_062818.1
	SLCO1B3-SLCO1B7	NM_001371097.1		c.767G>C	p.Gly256Ala	missense	Exon 7 of 16	NP_001358026.1
	SLCO1B3	NM_001349920.2		c.683G>C	p.Gly228Ala	missense	Exon 7 of 14	NP_001336849.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	ENST00000381545.8	TSL:2 MANE Select	c.767G>C	p.Gly256Ala	missense	Exon 9 of 16	ENSP00000370956.4
	SLCO1B3-SLCO1B7	ENST00000540229.1	TSL:2	c.767G>C	p.Gly256Ala	missense	Exon 7 of 16	ENSP00000441269.1
	SLCO1B3	ENST00000261196.6	TSL:1	c.767G>C	p.Gly256Ala	missense	Exon 7 of 14	ENSP00000261196.2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15920 AN: 151906 Hom.: 1134 Cov.: 32

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.112 AC: 28155 AN: 250862 AF XY: 0.116

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0739

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.000545

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.134 AC: 195800 AN: 1460420 Hom.: 14884 Cov.: 33 AF XY: 0.134 AC XY: 97076 AN XY: 726574

African (AFR) AF: 0.0249 AC: 831 AN: 33422

American (AMR) AF: 0.0771 AC: 3436 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 5137 AN: 26114

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39674

South Asian (SAS) AF: 0.0676 AC: 5818 AN: 86070

European-Finnish (FIN) AF: 0.106 AC: 5664 AN: 53412

Middle Eastern (MID) AF: 0.235 AC: 1353 AN: 5760

European-Non Finnish (NFE) AF: 0.149 AC: 165552 AN: 1111054

Other (OTH) AF: 0.132 AC: 7992 AN: 60328

GnomAD4 genome AF: 0.105 AC: 15914 AN: 152024 Hom.: 1132 Cov.: 32 AF XY: 0.100 AC XY: 7456 AN XY: 74336

African (AFR) AF: 0.0291 AC: 1206 AN: 41488

American (AMR) AF: 0.109 AC: 1669 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 670 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.0681 AC: 328 AN: 4818

European-Finnish (FIN) AF: 0.102 AC: 1078 AN: 10584

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10430 AN: 67906

Other (OTH) AF: 0.136 AC: 288 AN: 2110

Alfa AF: 0.127 Hom.: 494

Bravo AF: 0.104

TwinsUK AF: 0.146 AC: 540

ALSPAC AF: 0.147 AC: 566

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.156 AC: 1344

ExAC AF: 0.113 AC: 13739

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.163

EpiControl AF: 0.170

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Rotor syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.87
MPC		0.035
ClinPred		0.064	T
GERP RS		3.9
Varity_R		0.97
gMVP		0.77
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs60140950; hg19: chr12-21028208; COSMIC: COSV53935895;