rs61612406

Variant names:

• chr12-20815749-A-G
• rs61612406
• NM_019844.4:c.11A>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.11A>G​(p.His4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,590,812 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.231
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028271973).
• BP6: Variant 12-20815749-A-G is Benign according to our data. Variant chr12-20815749-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376892.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 = 0.0067 (1021/152334) while in subpopulation AFR AF = 0.0237 (987/41582). AF 95% confidence interval is 0.0225. There are 13 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.11A>G	p.His4Arg	missense	Exon 3 of 16	NP_062818.1
	SLCO1B3-SLCO1B7	NM_001371097.1		c.11A>G	p.His4Arg	missense	Exon 1 of 16	NP_001358026.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	ENST00000381545.8	TSL:2 MANE Select	c.11A>G	p.His4Arg	missense	Exon 3 of 16	ENSP00000370956.4
	SLCO1B3-SLCO1B7	ENST00000540229.1	TSL:2	c.11A>G	p.His4Arg	missense	Exon 1 of 16	ENSP00000441269.1
	SLCO1B3	ENST00000261196.6	TSL:1	c.11A>G	p.His4Arg	missense	Exon 1 of 14	ENSP00000261196.2

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1001 AN: 152216 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00166 AC: 393 AN: 237418 AF XY: 0.00118

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.000964

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000932

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.000636 AC: 915 AN: 1438478 Hom.: 12 Cov.: 28 AF XY: 0.000534 AC XY: 382 AN XY: 715812

African (AFR) AF: 0.0228 AC: 752 AN: 33030

American (AMR) AF: 0.000920 AC: 40 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 39194

South Asian (SAS) AF: 0.000192 AC: 16 AN: 83218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52396

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5646

European-Non Finnish (NFE) AF: 0.00000547 AC: 6 AN: 1096426

Other (OTH) AF: 0.00160 AC: 95 AN: 59332

GnomAD4 genome AF: 0.00670 AC: 1021 AN: 152334 Hom.: 13 Cov.: 33 AF XY: 0.00664 AC XY: 495 AN XY: 74506

African (AFR) AF: 0.0237 AC: 987 AN: 41582

American (AMR) AF: 0.00170 AC: 26 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00707

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00202 AC: 7 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.6
DANN	Benign	0.51
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.23
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.010
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.17	B
Vest4		0.076
MVP		0.13
MPC		0.0067
ClinPred		0.0046	T
GERP RS		-0.77
PromoterAI		0.025	Neutral
Varity_R		0.033
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: rs61612406; hg19: chr12-20968683;