12-20883534-T-C

Variant names:

• chr12-20883534-T-C
• rs77851390
• NM_019844.4:c.1614T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_019844.4(SLCO1B3):​c.1614T>C​(p.Val538Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,605,556 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SLCO1B3 NM_019844.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.630
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-20883534-T-C is Benign according to our data. Variant chr12-20883534-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 307908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.63 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1614T>C	p.Val538Val	synonymous	Exon 13 of 16	NP_062818.1
	SLCO1B3-SLCO1B7	NM_001371097.1		c.1614T>C	p.Val538Val	synonymous	Exon 11 of 16	NP_001358026.1
	SLCO1B3	NM_001349920.2		c.1530T>C	p.Val510Val	synonymous	Exon 11 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.1614T>C	p.Val538Val	synonymous	Exon 13 of 16	ENSP00000370956.4
	SLCO1B3-SLCO1B7	ENST00000540229.1	TSL:2	c.1614T>C	p.Val538Val	synonymous	Exon 11 of 16	ENSP00000441269.1
	SLCO1B3	ENST00000261196.6	TSL:1	c.1614T>C	p.Val538Val	synonymous	Exon 11 of 14	ENSP00000261196.2

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152196 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000586 AC: 142 AN: 242498 AF XY: 0.000495

Gnomad AFR exome AF: 0.00850

Gnomad AMR exome AF: 0.000314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000293 AC: 426 AN: 1453242 Hom.: 0 Cov.: 31 AF XY: 0.000261 AC XY: 189 AN XY: 723012

African (AFR) AF: 0.0112 AC: 369 AN: 32806

American (AMR) AF: 0.000397 AC: 17 AN: 42784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39022

South Asian (SAS) AF: 0.00 AC: 0 AN: 84624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108880

Other (OTH) AF: 0.000533 AC: 32 AN: 60026

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152314 Hom.: 4 Cov.: 33 AF XY: 0.00222 AC XY: 165 AN XY: 74482

African (AFR) AF: 0.00866 AC: 360 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00291

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Rotor syndrome (2)
-	-	1	not provided (1)
-	-	1	SLCO1B3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.39
DANN	Benign	0.77
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs77851390; hg19: chr12-21036468;