12-71125393-G-A

Variant names:

• chr12-71125393-G-A
• rs11178636
• NM_004616.3:c.661-6C>T

Variant summary

Our verdict is Benign. The variant received -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, 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, 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN8	NM_004616.3	c.661-6C>T		splice_region_variant, intron_variant	Intron 8 of 8	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1	c.661-6C>T		splice_region_variant, intron_variant	Intron 7 of 7		NP_001356689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN8	ENST00000247829.8	c.661-6C>T		splice_region_variant, intron_variant	Intron 8 of 8	1	NM_004616.3	ENSP00000247829.3
TSPAN8	ENST00000393330.6	c.661-6C>T		splice_region_variant, intron_variant	Intron 11 of 11	1		ENSP00000377003.2
TSPAN8	ENST00000546561.2	c.661-6C>T		splice_region_variant, intron_variant	Intron 7 of 7	1		ENSP00000447160.1
TSPAN8	ENST00000552128.2	n.525-6C>T		splice_region_variant, intron_variant	Intron 5 of 5	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

GnomAD2 exomes AF: 0.00807 AC: 1989 AN: 246476 AF XY: 0.00732

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 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 AC: 1468 AN: 33172

Gnomad4 AMR exome AF: 0.00289 AC: 126 AN: 43598

Gnomad4 ASJ exome AF: 0.00648 AC: 168 AN: 25924

Gnomad4 EAS exome AF: 0.0519 AC: 2056 AN: 39648

Gnomad4 SAS exome AF: 0.0102 AC: 866 AN: 85172

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53348

Gnomad4 NFE exome AF: 0.000122 AC: 135 AN: 1110036

Gnomad4 Remaining exome AF: 0.00725 AC: 436 AN: 60152

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 AC: 0.0413575 AN: 0.0413575

Gnomad4 AMR AF: 0.00471 AC: 0.00471328 AN: 0.00471328

Gnomad4 ASJ AF: 0.00634 AC: 0.00634006 AN: 0.00634006

Gnomad4 EAS AF: 0.0524 AC: 0.052357 AN: 0.052357

Gnomad4 SAS AF: 0.0137 AC: 0.0136986 AN: 0.0136986

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000382 AC: 0.000382285 AN: 0.000382285

Gnomad4 OTH AF: 0.0147 AC: 0.0146919 AN: 0.0146919

Alfa AF: 0.00640 Hom.: 8

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

May 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.8
DANN	Benign	0.53
Mutation Taster		=95/5	polymorphism (auto)

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;