12-20815946-A-T

Variant names:

• chr12-20815946-A-T
• rs74464403
• NM_019844.4:c.84+124A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019844.4(SLCO1B3):​c.84+124A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 491,284 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (127 hom., cov: 33)
  • Exomes 𝑓: 0.034 (304 hom.)
• Consequence: SLCO1B3 NM_019844.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.219
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-20815946-A-T is Benign according to our data. Variant chr12-20815946-A-T is described in ClinVar as [Benign]. Clinvar id is 1287212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.84+124A>T		intron_variant	Intron 3 of 15	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.84+124A>T		intron_variant	Intron 1 of 15		NP_001358026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.84+124A>T		intron_variant	Intron 3 of 15	2	NM_019844.4	ENSP00000370956.4
SLCO1B3-SLCO1B7	ENST00000540229.1	c.84+124A>T		intron_variant	Intron 1 of 15	2		ENSP00000441269.1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5459 AN: 152244 Hom.: 127 Cov.: 33

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.0991

Gnomad SAS AF: 0.0312

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0339 AC: 11476 AN: 338922 Hom.: 304 AF XY: 0.0327 AC XY: 5830 AN XY: 178188

African (AFR) AF: 0.0350 AC: 325 AN: 9282

American (AMR) AF: 0.0124 AC: 137 AN: 11040

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 641 AN: 11000

East Asian (EAS) AF: 0.104 AC: 2690 AN: 25900

South Asian (SAS) AF: 0.0139 AC: 300 AN: 21568

European-Finnish (FIN) AF: 0.0571 AC: 1439 AN: 25214

Middle Eastern (MID) AF: 0.0527 AC: 117 AN: 2222

European-Non Finnish (NFE) AF: 0.0246 AC: 5217 AN: 212278

Other (OTH) AF: 0.0299 AC: 610 AN: 20418

GnomAD4 genome AF: 0.0358 AC: 5458 AN: 152362 Hom.: 127 Cov.: 33 AF XY: 0.0374 AC XY: 2786 AN XY: 74506

African (AFR) AF: 0.0374 AC: 1556 AN: 41584

American (AMR) AF: 0.0186 AC: 284 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3470

East Asian (EAS) AF: 0.0988 AC: 512 AN: 5184

South Asian (SAS) AF: 0.0304 AC: 147 AN: 4832

European-Finnish (FIN) AF: 0.0644 AC: 684 AN: 10624

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0286 AC: 1943 AN: 68036

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0196 Hom.: 9

Bravo AF: 0.0319

Asia WGS AF: 0.0590 AC: 205 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.64
PhyloP100		0.22
PromoterAI		0.0012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74464403; hg19: chr12-20968880;