12-21019351-G-C

Variant names:

• chr12-21019351-G-C
• rs201467702
• ENST00000540229.1:c.1866-47968G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001371097.1(SLCO1B3-SLCO1B7):​c.1866-47968G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,628 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (1 hom.)
• Consequence: SLCO1B3-SLCO1B7 NM_001371097.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.567

Genes affected

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]

LOC124902894 (HGNC:):

SLCO1B7 (HGNC:32934): (solute carrier organic anion transporter family member 1B7 (putative)) Predicted to enable bile acid transmembrane transporter activity and sodium-independent organic anion transmembrane transporter activity. Predicted to be involved in bile acid and bile salt transport and sodium-independent organic anion transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30617428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124902894	XM_047429949.1	c.189G>C	p.Leu63Phe	missense_variant	Exon 3 of 10		XP_047285905.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.1866-47968G>C		intron_variant	Intron 13 of 15		NP_001358026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B3-SLCO1B7	ENST00000540229.1	c.1866-47968G>C		intron_variant	Intron 13 of 15	2		ENSP00000441269.1
SLCO1B3-SLCO1B7	ENST00000381541.7	c.360-2110G>C		intron_variant	Intron 3 of 13	2		ENSP00000370952.3
SLCO1B7	ENST00000648739.1	n.330G>C		non_coding_transcript_exon_variant	Exon 3 of 14

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251214 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135824

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461348 Hom.: 1 Cov.: 30 AF XY: 0.0000757 AC XY: 55 AN XY: 726990

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74460

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.189G>C (p.L63F) alteration is located in exon 2 (coding exon 2) of the SLCO1B7 gene. This alteration results from a G to C substitution at nucleotide position 189, causing the leucine (L) at amino acid position 63 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	0.0028
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.4	M
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.73		Gain of catalytic residue at S61 (P = 0);
MVP		0.13
MPC		0.027
ClinPred		0.50	D
GERP RS		-0.11
Varity_R		0.40
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs201467702; hg19: chr12-21172285; COSMIC: COSV67442576;