rs777571204

Variant names:

• chrX-100633518-C-A
• rs777571204
• NM_003270.4:c.472G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-100633518-C-A
• chrX-100633518-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003270.4(TSPAN6):​c.472G>T​(p.Asp158Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,087,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D158N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: TSPAN6 NM_003270.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.585
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2638254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN6	NM_003270.4	c.472G>T	p.Asp158Tyr	missense_variant	Exon 5 of 8	ENST00000373020.9	NP_003261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN6	ENST00000373020.9	c.472G>T	p.Asp158Tyr	missense_variant	Exon 5 of 8	1	NM_003270.4	ENSP00000362111.4
TSPAN6	ENST00000612152.4	c.208G>T	p.Asp70Tyr	missense_variant	Exon 5 of 7	5		ENSP00000482130.1
TSPAN6	ENST00000494424.1	n.744G>T		non_coding_transcript_exon_variant	Exon 6 of 6	2
TSPAN6	ENST00000496771.5	n.884G>T		non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000118 AC: 2 AN: 170012 AF XY: 0.0000174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000155

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1087455 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 354745

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

African (AFR) AF: 0.00 AC: 0 AN: 25832

American (AMR) AF: 0.00 AC: 0 AN: 32978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18860

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 30037

South Asian (SAS) AF: 0.00 AC: 0 AN: 51548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4057

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838185

Other (OTH) AF: 0.00 AC: 0 AN: 45592

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.24	.;T;T
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.78	T;D;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.34	.;N;.
PhyloP100		-0.58
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	.;D;.
REVEL	Benign	0.24
Sift	Benign	0.052	.;T;.
Sift4G	Benign	0.076	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.31
MutPred		0.78		.;Loss of catalytic residue at D158 (P = 0.1026);.;
MVP		0.81
MPC		0.077
ClinPred		0.13	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.86
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777571204; hg19: chrX-99888515; COSMIC: COSV107479355;