Genetic Variant TSPAN6:p.Asp138Val (chrX-100633968-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003270.4(TSPAN6):c.413A>T(p.Asp138Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000915 in 1,093,387 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

TSPAN6
NM_003270.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

Publications

0 publications found

Variant links:

Genes affected

TSPAN6 (HGNC:11858): (tetraspanin 6) 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. The protein encoded by this gene is a cell surface glycoprotein and is highly similar in sequence to the transmembrane 4 superfamily member 2 protein. It functions as a negative regulator of retinoic acid-inducible gene I-like receptor-mediated immune signaling via its interaction with the mitochondrial antiviral signaling-centered signalosome. This gene uses alternative polyadenylation sites, and multiple transcript variants result from alternative splicing. [provided by RefSeq, Jul 2013]

TSPAN6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN6	NM_003270.4 link	c.413A>T	p.Asp138Val	missense_variant	Exon 4 of 8	ENST00000373020.9	NP_003261.1	O43657

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPAN6	ENST00000373020.9 link	c.413A>T	p.Asp138Val	missense_variant	Exon 4 of 8	1	NM_003270.4	ENSP00000362111.4	O43657
TSPAN6	ENST00000612152.4 link	c.149A>T	p.Asp50Val	missense_variant	Exon 4 of 7	5		ENSP00000482130.1	A0A087WYV6
TSPAN6	ENST00000494424.1 link	n.685A>T		non_coding_transcript_exon_variant	Exon 5 of 6	2
TSPAN6	ENST00000496771.5 link	n.825A>T		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1093387

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359145

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26333

American (AMR)

AF:

0.00

AC:

AN:

35160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19355

East Asian (EAS)

AF:

0.00

AC:

AN:

30162

South Asian (SAS)

AF:

0.00

AC:

AN:

53880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838458

Other (OTH)

AF:

0.00

AC:

AN:

45956

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

Aug 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.413A>T (p.D138V) alteration is located in exon 4 (coding exon 4) of the TSPAN6 gene. This alteration results from a A to T substitution at nucleotide position 413, causing the aspartic acid (D) at amino acid position 138 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

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

T;T;T

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.6

.;M;.

PhyloP100

4.6

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.8

.;D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

.;D;.

Sift4G

Uncertain

0.028

D;D;D

Polyphen

0.17

.;B;.

Vest4

0.28

MutPred

0.54

.;Loss of disorder (P = 0.0112);.;

MVP

0.93

MPC

0.11

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.85

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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chrX-100633968-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over