12-20813517-T-G

Variant names:

• chr12-20813517-T-G
• rs76069495
• NM_019844.4:c.-180-7T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019844.4(SLCO1B3):​c.-180-7T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.037 in 152,262 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (103 hom., cov: 32)
  • Exomes 𝑓: 0.083 (0 hom.)
• Consequence: SLCO1B3 NM_019844.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009557
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.162
• 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 Gene-Disease associations (from GenCC):

• Rotor syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-20813517-T-G is Benign according to our data. Variant chr12-20813517-T-G is described in ClinVar as Benign. ClinVar VariationId is 307882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

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.-180-7T>G		splice_region intron	N/A	NP_062818.1	Q9NPD5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	ENST00000381545.8	TSL:2 MANE Select	c.-180-7T>G		splice_region intron	N/A	ENSP00000370956.4	Q9NPD5-1
	SLCO1B3	ENST00000540853.5	TSL:1	c.-65-2157T>G		intron	N/A	ENSP00000442000.1	F5H8K0
	SLCO1B3	ENST00000901222.1		c.-95-92T>G		intron	N/A	ENSP00000571281.1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5631 AN: 152132 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0398

Gnomad OTH AF: 0.0469

GnomAD4 exome AF: 0.0833 AC: 1 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.167 AC: 1 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0370 AC: 5626 AN: 152250 Hom.: 103 Cov.: 32 AF XY: 0.0366 AC XY: 2726 AN XY: 74436

African (AFR) AF: 0.0342 AC: 1419 AN: 41550

American (AMR) AF: 0.0381 AC: 582 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0748 AC: 360 AN: 4816

European-Finnish (FIN) AF: 0.0265 AC: 281 AN: 10612

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0398 AC: 2706 AN: 68014

Other (OTH) AF: 0.0469 AC: 99 AN: 2110

Alfa AF: 0.0310 Hom.: 44

Bravo AF: 0.0368

Asia WGS AF: 0.0330 AC: 116 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.5
DANN	Benign	0.75
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.11		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: rs76069495; hg19: chr12-20966451;