12-71125393-G-A

Position:

• chr12-71125393-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004616.3(TSPAN8):​c.661-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 1,608,940 control chromosomes in the GnomAD database, including 173 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 0.014 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (138 hom.)
• Consequence: TSPAN8 NM_004616.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002133
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15

Genes affected

TSPAN8 (HGNC:11855): (tetraspanin 8) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This gene is expressed in different carcinomas. The use of alternate polyadenylation sites has been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-71125393-G-A is Benign according to our data. Variant chr12-71125393-G-A is described in ClinVar as [Benign]. Clinvar id is 779949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0145 (2205/152172) while in subpopulation EAS AF= 0.0524 (271/5176). AF 95% confidence interval is 0.0472. There are 35 homozygotes in gnomad4. There are 1085 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN8	NM_004616.3	c.661-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000247829.8
TSPAN8	NM_001369760.1	c.661-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN8	ENST00000247829.8	c.661-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004616.3	P1
TSPAN8	ENST00000393330.6	c.661-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
TSPAN8	ENST00000546561.2	c.661-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
TSPAN8	ENST00000552128.2	n.525-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2197 AN: 152054 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0522

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00807 AC: 1989 AN: 246476 Hom.: 40 AF XY: 0.00732 AC XY: 975 AN XY: 133240

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00520

Gnomad EAS exome AF: 0.0443

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000250

Gnomad OTH exome AF: 0.00634

GnomAD4 exome AF: 0.00361 AC: 5265 AN: 1456768 Hom.: 138 Cov.: 30 AF XY: 0.00364 AC XY: 2641 AN XY: 724680

Gnomad4 AFR exome AF: 0.0443

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.00648

Gnomad4 EAS exome AF: 0.0519

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.00725

GnomAD4 genome AF: 0.0145 AC: 2205 AN: 152172 Hom.: 35 Cov.: 32 AF XY: 0.0146 AC XY: 1085 AN XY: 74404

Gnomad4 AFR AF: 0.0414

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0524

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00667 Hom.: 5

Bravo AF: 0.0160

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.8
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs11178636; hg19: chr12-71519173; COSMIC: COSV56080120;