12-20815731-GTTTA-G

Variant names:

• chr12-20815731-GTTTA-G
• rs4149158
• NM_019844.4:c.-7_-4delTTTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_019844.4(SLCO1B3):​c.-7_-4delTTTA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,547,798 control chromosomes in the GnomAD database, including 55,692 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4630 hom., cov: 24)
  • Exomes 𝑓: 0.26 (51062 hom.)
• Consequence: SLCO1B3 NM_019844.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.21
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 12-20815731-GTTTA-G is Benign according to our data. Variant chr12-20815731-GTTTA-G is described in ClinVar as [Benign]. Clinvar id is 440287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.-7_-4delTTTA		5_prime_UTR_variant	Exon 3 of 16	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.-7_-4delTTTA		5_prime_UTR_variant	Exon 1 of 16		NP_001358026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.-7_-4delTTTA		5_prime_UTR_variant	Exon 3 of 16	2	NM_019844.4	ENSP00000370956.4
SLCO1B3-SLCO1B7	ENST00000540229.1	c.-7_-4delTTTA		5_prime_UTR_variant	Exon 1 of 16	2		ENSP00000441269.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35586 AN: 151966 Hom.: 4631 Cov.: 24

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.154 AC: 31904 AN: 207762 AF XY: 0.162

Gnomad AFR exome AF: 0.0802

Gnomad AMR exome AF: 0.0759

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0846

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.261 AC: 364166 AN: 1395712 Hom.: 51062 AF XY: 0.259 AC XY: 179963 AN XY: 694372

African (AFR) AF: 0.117 AC: 3767 AN: 32238

American (AMR) AF: 0.150 AC: 6254 AN: 41730

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 6008 AN: 24970

East Asian (EAS) AF: 0.155 AC: 6025 AN: 38754

South Asian (SAS) AF: 0.132 AC: 10541 AN: 79678

European-Finnish (FIN) AF: 0.240 AC: 12328 AN: 51292

Middle Eastern (MID) AF: 0.372 AC: 2017 AN: 5426

European-Non Finnish (NFE) AF: 0.284 AC: 302417 AN: 1063962

Other (OTH) AF: 0.257 AC: 14809 AN: 57662

GnomAD4 genome AF: 0.234 AC: 35612 AN: 152086 Hom.: 4630 Cov.: 24 AF XY: 0.231 AC XY: 17146 AN XY: 74340

African (AFR) AF: 0.135 AC: 5621 AN: 41494

American (AMR) AF: 0.221 AC: 3373 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3472

East Asian (EAS) AF: 0.170 AC: 880 AN: 5178

South Asian (SAS) AF: 0.161 AC: 775 AN: 4820

European-Finnish (FIN) AF: 0.255 AC: 2685 AN: 10526

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20385 AN: 67992

Other (OTH) AF: 0.262 AC: 554 AN: 2116

Alfa AF: 0.106 Hom.: 449

Asia WGS AF: 0.162 AC: 558 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:1

Nov 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 5

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

Other links and lift over

dbSNP: rs4149158; hg19: chr12-20968665; COSMIC: COSV53933022;