X-100633463-C-T

Position:

• chrX-100633463-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003270.4(TSPAN6):​c.527G>A​(p.Ser176Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,439 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TSPAN6 NM_003270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN6	NM_003270.4	c.527G>A	p.Ser176Asn	missense_variant	5/8	ENST00000373020.9	NP_003261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN6	ENST00000373020.9	c.527G>A	p.Ser176Asn	missense_variant	5/8	1	NM_003270.4	ENSP00000362111.4
TSPAN6	ENST00000612152.4	c.263G>A	p.Ser88Asn	missense_variant	5/7	5		ENSP00000482130.1
TSPAN6	ENST00000494424.1	n.799G>A		non_coding_transcript_exon_variant	6/6	2
TSPAN6	ENST00000496771.5	n.939G>A		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094439 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 359875

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2024

The c.527G>A (p.S176N) alteration is located in exon 5 (coding exon 5) of the TSPAN6 gene. This alteration results from a G to A substitution at nucleotide position 527, causing the serine (S) at amino acid position 176 to be replaced by an asparagine (N). 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	0.88
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;D;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	.;H;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	.;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	.;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.69
MutPred		0.86		.;Gain of ubiquitination at K179 (P = 0.1093);.;
MVP		0.33
MPC		0.34
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-99888460;