NM_003270.4:c.472G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003270.4(TSPAN6):​c.472G>A​(p.Asp158Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000584 in 1,198,730 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: TSPAN6 NM_003270.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02628249).
• BP6: Variant X-100633518-C-T is Benign according to our data. Variant chrX-100633518-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3183848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN6	NM_003270.4	c.472G>A	p.Asp158Asn	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>A	p.Asp158Asn	missense_variant	Exon 5 of 8	1	NM_003270.4	ENSP00000362111.4
TSPAN6	ENST00000612152.4	c.208G>A	p.Asp70Asn	missense_variant	Exon 5 of 7	5		ENSP00000482130.1
TSPAN6	ENST00000494424.1	n.744G>A		non_coding_transcript_exon_variant	Exon 6 of 6	2
TSPAN6	ENST00000496771.5	n.884G>A		non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111273 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000391

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000460 AC: 5 AN: 1087457 Hom.: 0 Cov.: 29 AF XY: 0.00000564 AC XY: 2 AN XY: 354745

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: 0.00 AC: 0 AN: 30037

South Asian (SAS) AF: 0.0000388 AC: 2 AN: 51550

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: 0.00000358 AC: 3 AN: 838185

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

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111273 Hom.: 0 Cov.: 22 AF XY: 0.0000598 AC XY: 2 AN XY: 33463

African (AFR) AF: 0.00 AC: 0 AN: 30625

American (AMR) AF: 0.00 AC: 0 AN: 10437

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.000391 AC: 1 AN: 2559

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5943

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53088

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 16, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.29
DANN	Benign	0.45
DEOGEN2	Benign	0.063	.;T;T
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-2.5	.;N;.
PhyloP100		-0.58
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.3	.;N;.
REVEL	Benign	0.16
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.10
MutPred		0.69		.;Loss of catalytic residue at D158 (P = 0.0815);.;
MVP		0.57
MPC		0.052
ClinPred		0.032	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.58
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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;