12-71129354-A-C

Position:

• chr12-71129354-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004616.3(TSPAN8):​c.637T>G​(p.Ser213Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,572,296 control chromosomes in the GnomAD database, including 115,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (8469 hom., cov: 31)
  • Exomes 𝑓: 0.38 (107226 hom.)
• Consequence: TSPAN8 NM_004616.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029125214).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN8	NM_004616.3	c.637T>G	p.Ser213Ala	missense_variant	8/9	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1	c.637T>G	p.Ser213Ala	missense_variant	7/8		NP_001356689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN8	ENST00000247829.8	c.637T>G	p.Ser213Ala	missense_variant	8/9	1	NM_004616.3	ENSP00000247829	P1
TSPAN8	ENST00000393330.6	c.637T>G	p.Ser213Ala	missense_variant	11/12	1		ENSP00000377003	P1
TSPAN8	ENST00000546561.2	c.637T>G	p.Ser213Ala	missense_variant	7/8	1		ENSP00000447160	P1
TSPAN8	ENST00000552128.2	n.501T>G		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes AF: 0.318 AC: 47910 AN: 150822 Hom.: 8464 Cov.: 31

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.336 AC: 76898 AN: 229084 Hom.: 14288 AF XY: 0.347 AC XY: 42987 AN XY: 124008

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.295

Gnomad SAS exome AF: 0.287

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.381 AC: 542199 AN: 1421378 Hom.: 107226 Cov.: 33 AF XY: 0.381 AC XY: 269447 AN XY: 706896

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.308

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.354

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.318 AC: 47922 AN: 150918 Hom.: 8469 Cov.: 31 AF XY: 0.313 AC XY: 23018 AN XY: 73636

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.447

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.279

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.342

Alfa AF: 0.396 Hom.: 30676

Bravo AF: 0.307

TwinsUK AF: 0.413 AC: 1531

ALSPAC AF: 0.419 AC: 1614

ESP6500AA AF: 0.189 AC: 832

ESP6500EA AF: 0.410 AC: 3526

ExAC AF: 0.341 AC: 41401

Asia WGS AF: 0.260 AC: 900 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.36
DEOGEN2	Benign	0.018	T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.17	.;.;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.8	N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.7	N;N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.027
MPC		0.072
ClinPred		0.0023	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.72

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: rs1051334; hg19: chr12-71523134; COSMIC: COSV56081147;