chr12-20815821-A-C

Position:

• chr12-20815821-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 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

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLCO1B3	NM_019844.4	c.83A>C	p.Lys28Thr	missense_variant, splice_region_variant	3/16	ENST00000381545.8
SLCO1B3-SLCO1B7	NM_001371097.1	c.83A>C	p.Lys28Thr	missense_variant, splice_region_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.83A>C	p.Lys28Thr	missense_variant, splice_region_variant	3/16	2	NM_019844.4	P1
SLCO1B3	ENST00000261196.6	c.83A>C	p.Lys28Thr	missense_variant, splice_region_variant	1/14	1		P1
SLCO1B3	ENST00000540853.5	c.83A>C	p.Lys28Thr	missense_variant, splice_region_variant	2/8	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000864 AC: 2 AN: 231500 Hom.: 0 AF XY: 0.00000797 AC XY: 1 AN XY: 125504

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 SAS exome AF: 0.0000748

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rotor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.83A>C (p.Lys28Thr) variant in SLCO1B3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.0008% in the gnomAD and novel in 1000 genome database. The amino acid Lys at position 28 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Lys28Thr in SLCO1B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. In the absence of second reportable variant , the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.88	D;.;D;D;T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.6	.;H;H;.;.
MutationTaster	Benign	0.71	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.58, 0.58, 0.62, 0.59
MutPred		0.62		Loss of methylation at K28 (P = 0.0027);Loss of methylation at K28 (P = 0.0027);Loss of methylation at K28 (P = 0.0027);Loss of methylation at K28 (P = 0.0027);Loss of methylation at K28 (P = 0.0027);
MVP		0.48
MPC		0.032, 0.043
ClinPred		0.97	D
GERP RS		0.69
Varity_R		0.50
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs563634489; hg19: chr12-20968755;