12-71144173-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004616.3(TSPAN8):​c.101G>T​(p.Arg34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN8	NM_004616.3	c.101G>T	p.Arg34Leu	missense_variant	Exon 3 of 9	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1	c.101G>T	p.Arg34Leu	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>T	p.Arg34Leu	missense_variant	Exon 3 of 9	1	NM_004616.3	ENSP00000247829.3
TSPAN8	ENST00000393330.6	c.101G>T	p.Arg34Leu	missense_variant	Exon 6 of 12	1		ENSP00000377003.2
TSPAN8	ENST00000546561.2	c.101G>T	p.Arg34Leu	missense_variant	Exon 2 of 8	1		ENSP00000447160.1
TSPAN8	ENST00000552786.1	n.360G>T		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	0.054
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	.;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.70
MutPred		0.67		Loss of catalytic residue at R34 (P = 0.0799);Loss of catalytic residue at R34 (P = 0.0799);Loss of catalytic residue at R34 (P = 0.0799);
MVP		0.92
MPC		0.52
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.59
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -22

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;