Genetic Variant TSPAN8:p.Ala28Thr (chr12-71144192-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004616.3(TSPAN8):c.82G>A(p.Ala28Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TSPAN8
NM_004616.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

Variant links:

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]

TSPAN8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36069518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN8	NM_004616.3 link	c.82G>A	p.Ala28Thr	missense_variant	Exon 3 of 9	ENST00000247829.8	NP_004607.1	P19075
TSPAN8	NM_001369760.1 link	c.82G>A	p.Ala28Thr	missense_variant	Exon 2 of 8		NP_001356689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPAN8	ENST00000247829.8 link	c.82G>A	p.Ala28Thr	missense_variant	Exon 3 of 9	1	NM_004616.3	ENSP00000247829.3	P19075
TSPAN8	ENST00000393330.6 link	c.82G>A	p.Ala28Thr	missense_variant	Exon 6 of 12	1		ENSP00000377003.2	P19075
TSPAN8	ENST00000546561.2 link	c.82G>A	p.Ala28Thr	missense_variant	Exon 2 of 8	1		ENSP00000447160.1	P19075
TSPAN8	ENST00000552786.1 link	n.341G>A		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249308

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82G>A (p.A28T) alteration is located in exon 3 (coding exon 2) of the TSPAN8 gene. This alteration results from a G to A substitution at nucleotide position 82, causing the alanine (A) at amino acid position 28 to be replaced by a threonine (T). 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

0.21

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.75

.;.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.72

P;P;P

Vest4

0.13

MutPred

0.75

Loss of stability (P = 0.1048);Loss of stability (P = 0.1048);Loss of stability (P = 0.1048);

MVP

0.44

MPC

0.31

ClinPred

0.72

GERP RS

2.4

Varity_R

0.25

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over