12-20855146-T-TAATTG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_019844.4(SLCO1B3):c.205_209dup(p.Asp70GlufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,609,310 control chromosomes in the GnomAD database, including 34 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (27 hom.)
• Consequence: SLCO1B3 NM_019844.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: -0.751

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High Homozygotes in GnomAd at 7 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLCO1B3	NM_019844.4	c.205_209dup	p.Asp70GlufsTer13	frameshift_variant	4/16	ENST00000381545.8
SLCO1B3-SLCO1B7	NM_001371097.1	c.205_209dup	p.Asp70GlufsTer13	frameshift_variant	2/16
SLCO1B3	NM_001349920.2	c.121_125dup	p.Asp42GlufsTer13	frameshift_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.205_209dup	p.Asp70GlufsTer13	frameshift_variant	4/16	2	NM_019844.4	P1
SLCO1B3	ENST00000261196.6	c.205_209dup	p.Asp70GlufsTer13	frameshift_variant	2/14	1		P1
SLCO1B3	ENST00000540853.5	c.205_209dup	p.Asp70GlufsTer13	frameshift_variant	3/8	1
SLCO1B3	ENST00000545880.1	n.57_61dup		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 579 AN: 152236 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00416 AC: 1024 AN: 245910 Hom.: 9 AF XY: 0.00409 AC XY: 544 AN XY: 132962

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00600

GnomAD4 exome AF: 0.00348 AC: 5072 AN: 1456956 Hom.: 27 Cov.: 30 AF XY: 0.00347 AC XY: 2518 AN XY: 724844

Gnomad4 AFR exome AF: 0.000513

Gnomad4 AMR exome AF: 0.000344

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.00325

Gnomad4 OTH exome AF: 0.00299

GnomAD4 genome AF: 0.00380 AC: 579 AN: 152354 Hom.: 7 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74496

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00398 Hom.: 4

Bravo AF: 0.00237

EpiCase AF: 0.00278

EpiControl AF: 0.00268

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rotor syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2022	The SLCO1B3 c.205_209dup; p.Asp70GlufsTer13 variant (rs558592800) is reported in the literature as one among several variants in one family with autism spectrum disorder, but with no details on hemolytic anemia or related phenotype (Yuen 2015). This variant is also reported in ClinVar (Variation ID: 712105). This variant is found in the general population with an overall allele frequency of 0.4% (1243/277294 alleles, including 13 homozygotes) in the Genome Aggregation Database. This variant causes a frameshift by inserting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 03, 2018

- -

SLCO1B3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs558592800; hg19: chr12-21008080;