NM_004616.3:c.703G>A

Variant names:

• chr12-71125345-C-T
• rs144070931
• NM_004616.3:c.703G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004616.3(TSPAN8):​c.703G>A​(p.Gly235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,612,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: TSPAN8 NM_004616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.344
• Publications: 0 publications found

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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004616.3. 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
	TSPAN8	NM_004616.3	MANE Select	c.703G>A	p.Gly235Arg	missense	Exon 9 of 9	NP_004607.1	P19075
	TSPAN8	NM_001369760.1		c.703G>A	p.Gly235Arg	missense	Exon 8 of 8	NP_001356689.1	P19075

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN8	ENST00000247829.8	TSL:1 MANE Select	c.703G>A	p.Gly235Arg	missense	Exon 9 of 9	ENSP00000247829.3	P19075
	TSPAN8	ENST00000393330.6	TSL:1	c.703G>A	p.Gly235Arg	missense	Exon 12 of 12	ENSP00000377003.2	P19075
	TSPAN8	ENST00000546561.2	TSL:1	c.703G>A	p.Gly235Arg	missense	Exon 8 of 8	ENSP00000447160.1	P19075

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000480 AC: 12 AN: 250014 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000918 AC: 134 AN: 1460078 Hom.: 0 Cov.: 30 AF XY: 0.0000991 AC XY: 72 AN XY: 726348

African (AFR) AF: 0.0000300 AC: 1 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85904

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1111260

Other (OTH) AF: 0.000133 AC: 8 AN: 60300

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74234

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00018	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N
PhyloP100		0.34
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.11
Sift	Benign	0.12	T
Sift4G	Benign	0.87	T
Polyphen		0.99	D
Vest4		0.044
MutPred		0.25		Gain of MoRF binding (P = 0.0341)
MVP		0.73
MPC		0.23
ClinPred		0.16	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.46
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144070931; hg19: chr12-71519125;