chr12-71144173-C-G

Variant names:

• chr12-71144173-C-G
• rs372283008
• NM_004616.3:c.101G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004616.3(TSPAN8):​c.101G>C​(p.Arg34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSPAN8 NM_004616.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN8	NM_004616.3	c.101G>C	p.Arg34Pro	missense_variant	Exon 3 of 9	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1	c.101G>C	p.Arg34Pro	missense_variant	Exon 2 of 8		NP_001356689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN8	ENST00000247829.8	c.101G>C	p.Arg34Pro	missense_variant	Exon 3 of 9	1	NM_004616.3	ENSP00000247829.3
TSPAN8	ENST00000393330.6	c.101G>C	p.Arg34Pro	missense_variant	Exon 6 of 12	1		ENSP00000377003.2
TSPAN8	ENST00000546561.2	c.101G>C	p.Arg34Pro	missense_variant	Exon 2 of 8	1		ENSP00000447160.1
TSPAN8	ENST00000552786.1	n.360G>C		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152002 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459740 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.59	.;.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.1	H;H;H
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.78
MutPred		0.74		Gain of glycosylation at S36 (P = 0.0545);Gain of glycosylation at S36 (P = 0.0545);Gain of glycosylation at S36 (P = 0.0545);
MVP		0.91
MPC		0.56
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.99
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs372283008; hg19: chr12-71537953;