12-71144183-T-C

Variant names:

• chr12-71144183-T-C
• NM_004616.3:c.91A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004616.3(TSPAN8):​c.91A>G​(p.Ile31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPAN8 NM_004616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN8	NM_004616.3	c.91A>G	p.Ile31Val	missense_variant	Exon 3 of 9	ENST00000247829.8	NP_004607.1
TSPAN8	NM_001369760.1	c.91A>G	p.Ile31Val	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.91A>G	p.Ile31Val	missense_variant	Exon 3 of 9	1	NM_004616.3	ENSP00000247829.3
TSPAN8	ENST00000393330.6	c.91A>G	p.Ile31Val	missense_variant	Exon 6 of 12	1		ENSP00000377003.2
TSPAN8	ENST00000546561.2	c.91A>G	p.Ile31Val	missense_variant	Exon 2 of 8	1		ENSP00000447160.1
TSPAN8	ENST00000552786.1	n.350A>G		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91A>G (p.I31V) alteration is located in exon 3 (coding exon 2) of the TSPAN8 gene. This alteration results from a A to G substitution at nucleotide position 91, causing the isoleucine (I) at amino acid position 31 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	.;.;T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.73	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.092	T;T;T
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.13
MutPred		0.65		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.66
MPC		0.35
ClinPred		0.81	D
GERP RS		4.2
Varity_R		0.22
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-71537963; COSMIC: COSV56078093; COSMIC: COSV56078093;