X-100636666-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003270.4(TSPAN6):c.29C>T(p.Thr10Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 1,203,859 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

TSPAN6
NM_003270.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.27

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN6	NM_003270.4 link	c.29C>T	p.Thr10Ile	missense_variant	Exon 1 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.29C>T	p.Thr10Ile	missense_variant	Exon 1 of 8	1	NM_003270.4	ENSP00000362111.4	O43657
TSPAN6	ENST00000496771.5 link	n.24C>T		non_coding_transcript_exon_variant	Exon 1 of 6	3
TSPAN6	ENST00000612152.4 link	c.-178+127C>T		intron_variant	Intron 1 of 6	5		ENSP00000482130.1	A0A087WYV6
TSPAN6	ENST00000494424.1 link	n.359+127C>T		intron_variant	Intron 2 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

112033

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000175

AC:

AN:

171742

AF XY:

0.0000175

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000232

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000641

AC:

AN:

1091826

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

357658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26242

American (AMR)

AF:

0.00

AC:

AN:

34694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19290

East Asian (EAS)

AF:

0.000234

AC:

AN:

29910

South Asian (SAS)

AF:

0.00

AC:

AN:

52395

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839028

Other (OTH)

AF:

0.00

AC:

AN:

45857

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000893

AC:

AN:

112033

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34171

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30816

American (AMR)

AF:

0.00

AC:

AN:

10629

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.000280

AC:

AN:

3568

South Asian (SAS)

AF:

0.00

AC:

AN:

2619

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53179

Other (OTH)

AF:

0.00

AC:

AN:

1504

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.29C>T (p.T10I) alteration is located in exon 1 (coding exon 1) of the TSPAN6 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the threonine (T) at amino acid position 10 to be replaced by an isoleucine (I). 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

Pathogenic

0.82

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.061

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.5

PhyloP100

8.3

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.26

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.98

Vest4

0.64

MutPred

0.32

Gain of catalytic residue at P12 (P = 0.0331);

MVP

0.11

MPC

0.13

ClinPred

0.82

GERP RS

3.8

PromoterAI

-0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.77

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-100636666-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over