rs3763978

Positions:

• chr12-71139754-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000247829.8(TSPAN8):​c.218G>C​(p.Gly73Ala) variant causes a missense change. The variant allele was found at a frequency of 0.373 in 1,612,202 control chromosomes in the GnomAD database, including 118,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7969 hom., cov: 32)
  • Exomes 𝑓: 0.38 (110187 hom.)
• Consequence: TSPAN8 ENST00000247829.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057137907).
• BP6: Variant 12-71139754-C-G is Benign according to our data. Variant chr12-71139754-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN8	NM_004616.3	c.218G>C	p.Gly73Ala	missense_variant	4/9	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1	c.218G>C	p.Gly73Ala	missense_variant	3/8		NP_001356689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN8	ENST00000247829.8	c.218G>C	p.Gly73Ala	missense_variant	4/9	1	NM_004616.3	ENSP00000247829	P1
TSPAN8	ENST00000393330.6	c.218G>C	p.Gly73Ala	missense_variant	7/12	1		ENSP00000377003	P1
TSPAN8	ENST00000546561.2	c.218G>C	p.Gly73Ala	missense_variant	3/8	1		ENSP00000447160	P1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44603 AN: 151926 Hom.: 7967 Cov.: 32

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.327

GnomAD3 exomes AF: 0.329 AC: 82526 AN: 250554 Hom.: 15208 AF XY: 0.342 AC XY: 46266 AN XY: 135422

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.300

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.381 AC: 556859 AN: 1460158 Hom.: 110187 Cov.: 41 AF XY: 0.381 AC XY: 276909 AN XY: 726328

Gnomad4 AFR exome AF: 0.0820

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.423

Gnomad4 EAS exome AF: 0.311

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.354

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.293 AC: 44601 AN: 152044 Hom.: 7969 Cov.: 32 AF XY: 0.290 AC XY: 21544 AN XY: 74326

Gnomad4 AFR AF: 0.0923

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.429

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.279

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.324

Alfa AF: 0.379 Hom.: 3840

Bravo AF: 0.280

TwinsUK AF: 0.410 AC: 1521

ALSPAC AF: 0.418 AC: 1612

ESP6500AA AF: 0.110 AC: 483

ESP6500EA AF: 0.410 AC: 3526

ExAC AF: 0.333 AC: 40448

Asia WGS AF: 0.254 AC: 881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	.;.;T
MetaRNN	Benign	0.0057	T;T;T
MetaSVM	Benign	-1.7	T
MutationAssessor	Pathogenic	3.6	H;H;H
MutationTaster	Benign	0.0000021	P;P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.67
Sift	Benign	0.033	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.26
MPC		0.47
ClinPred		0.055	T
GERP RS		5.1
Varity_R		0.72
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3763978; hg19: chr12-71533534; COSMIC: COSV56077446; COSMIC: COSV56077446;