rs77271279

chr12-21176898-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_006446.5(SLCO1B1):c.481+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.00162 in 1,547,080 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0086 (24 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (22 hom.)
• Consequence: SLCO1B1 NM_006446.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 4.25

Genes affected

SLCO1B1 (HGNC:10959): (solute carrier organic anion transporter family member 1B1) 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 numerous endogenous compounds including bilirubin, 17-beta-glucuronosyl estradiol and leukotriene C4. This protein is also involved in the removal of drug compounds such as statins, bromosulfophthalein and rifampin from the blood into the hepatocytes. Polymorphisms in the gene encoding this protein are associated with impaired transporter function. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, BayesDel_noAF, MutationTaster was below the threshold]
• BP6: Variant 12-21176898-G-T is Benign according to our data. Variant chr12-21176898-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 307938.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr12-21176898-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00862 (1311/152088) while in subpopulation AFR AF= 0.0297 (1233/41518). AF 95% confidence interval is 0.0283. There are 24 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLCO1B1	NM_006446.5	c.481+1G>T		splice_donor_variant		ENST00000256958.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B1	ENST00000256958.3	c.481+1G>T		splice_donor_variant		1	NM_006446.5	P1

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 1309 AN: 151970 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

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: 0.000162

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00235 AC: 589 AN: 250278 Hom.: 7 AF XY: 0.00185 AC XY: 250 AN XY: 135352

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.00211

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: 0.0000797

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000858 AC: 1197 AN: 1394992 Hom.: 22 Cov.: 27 AF XY: 0.000716 AC XY: 499 AN XY: 696988

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000468

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000285

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00862 AC: 1311 AN: 152088 Hom.: 24 Cov.: 33 AF XY: 0.00818 AC XY: 608 AN XY: 74362

Gnomad4 AFR AF: 0.0297

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00189 Hom.: 9

Bravo AF: 0.00959

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.00288 AC: 350

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rotor syndrome Pathogenic:1 Uncertain:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 26, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	30
Dann	Uncertain	0.98
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77271279; hg19: chr12-21329832;