NM_019844.4:c.83A>C

Variant names:

• chr12-20815821-A-C
• rs563634489
• NM_019844.4:c.83A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019844.4(SLCO1B3):​c.83A>C​(p.Lys28Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,419,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense, splice_region
• Scores: Splicing: ADA: 0.9980
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.83A>C	p.Lys28Thr	missense splice_region	Exon 3 of 16	NP_062818.1	Q9NPD5-1
	SLCO1B3-SLCO1B7	NM_001371097.1		c.83A>C	p.Lys28Thr	missense splice_region	Exon 1 of 16	NP_001358026.1	A0A0A6YYJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	ENST00000381545.8	TSL:2 MANE Select	c.83A>C	p.Lys28Thr	missense splice_region	Exon 3 of 16	ENSP00000370956.4	Q9NPD5-1
	SLCO1B3-SLCO1B7	ENST00000540229.1	TSL:2	c.83A>C	p.Lys28Thr	missense splice_region	Exon 1 of 16	ENSP00000441269.1
	SLCO1B3	ENST00000261196.6	TSL:1	c.83A>C	p.Lys28Thr	missense splice_region	Exon 1 of 14	ENSP00000261196.2	Q9NPD5-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000864 AC: 2 AN: 231500 AF XY: 0.00000797

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419706 Hom.: 0 Cov.: 26 AF XY: 0.00000283 AC XY: 2 AN XY: 706144

African (AFR) AF: 0.00 AC: 0 AN: 32382

American (AMR) AF: 0.00 AC: 0 AN: 41212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25252

East Asian (EAS) AF: 0.00 AC: 0 AN: 38924

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086860

Other (OTH) AF: 0.00 AC: 0 AN: 58544

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Rotor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.62		Loss of methylation at K28 (P = 0.0027)
MVP		0.48
MPC		0.032
ClinPred		0.97	D
GERP RS		0.69
PromoterAI		-0.025	Neutral
Varity_R		0.50
gMVP		0.53
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.070		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: rs563634489; hg19: chr12-20968755;