12-20861096-A-G

Variant names:

• chr12-20861096-A-G
• rs57585902
• NM_019844.4:c.439A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019844.4(SLCO1B3):​c.439A>G​(p.Thr147Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,602,552 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (9 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.999
• Publications: 11 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 (MetaRNN=0.0026707351).
• BP6: Variant 12-20861096-A-G is Benign according to our data. Variant chr12-20861096-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 307887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00894 (1361/152232) while in subpopulation AFR AF = 0.031 (1286/41536). AF 95% confidence interval is 0.0296. There are 14 homozygotes in GnomAd4. There are 639 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	NM_019844.4	MANE Select	c.439A>G	p.Thr147Ala	missense	Exon 6 of 16	NP_062818.1	Q9NPD5-1
	SLCO1B3-SLCO1B7	NM_001371097.1		c.439A>G	p.Thr147Ala	missense	Exon 4 of 16	NP_001358026.1	A0A0A6YYJ9
	SLCO1B3	NM_001349920.2		c.355A>G	p.Thr119Ala	missense	Exon 4 of 14	NP_001336849.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	ENST00000381545.8	TSL:2 MANE Select	c.439A>G	p.Thr147Ala	missense	Exon 6 of 16	ENSP00000370956.4	Q9NPD5-1
	SLCO1B3-SLCO1B7	ENST00000540229.1	TSL:2	c.439A>G	p.Thr147Ala	missense	Exon 4 of 16	ENSP00000441269.1
	SLCO1B3	ENST00000261196.6	TSL:1	c.439A>G	p.Thr147Ala	missense	Exon 4 of 14	ENSP00000261196.2	Q9NPD5-1

Frequencies

GnomAD3 genomes AF: 0.00894 AC: 1360 AN: 152114 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

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: 0.0000588

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00224 AC: 541 AN: 242006 AF XY: 0.00158

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000861 AC: 1248 AN: 1450320 Hom.: 9 Cov.: 31 AF XY: 0.000747 AC XY: 539 AN XY: 721486

African (AFR) AF: 0.0302 AC: 997 AN: 32976

American (AMR) AF: 0.00174 AC: 75 AN: 43024

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 83950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5732

European-Non Finnish (NFE) AF: 0.0000588 AC: 65 AN: 1106032

Other (OTH) AF: 0.00175 AC: 105 AN: 60006

GnomAD4 genome AF: 0.00894 AC: 1361 AN: 152232 Hom.: 14 Cov.: 33 AF XY: 0.00859 AC XY: 639 AN XY: 74432

African (AFR) AF: 0.0310 AC: 1286 AN: 41536

American (AMR) AF: 0.00379 AC: 58 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00307 Hom.: 6

Bravo AF: 0.0103

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0291 AC: 128

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000179

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.7
DANN	Benign	0.83
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.078	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.0
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.028
Sift	Benign	0.074	T
Sift4G	Benign	0.37	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.15
MPC		0.0071
ClinPred		0.0079	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.16
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: rs57585902; hg19: chr12-21014030; COSMIC: COSV104370159;