X-100635595-A-G

Variant names:

• chrX-100635595-A-G
• NM_003270.4:c.239T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003270.4(TSPAN6):​c.239T>C​(p.Phe80Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000921 in 1,086,300 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: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: TSPAN6 NM_003270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN6	NM_003270.4	c.239T>C	p.Phe80Ser	missense_variant	Exon 2 of 8	ENST00000373020.9	NP_003261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN6	ENST00000373020.9	c.239T>C	p.Phe80Ser	missense_variant	Exon 2 of 8	1	NM_003270.4	ENSP00000362111.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1086300 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 353102

African (AFR) AF: 0.00 AC: 0 AN: 26241

American (AMR) AF: 0.00 AC: 0 AN: 34543

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19139

East Asian (EAS) AF: 0.00 AC: 0 AN: 29971

South Asian (SAS) AF: 0.00 AC: 0 AN: 51674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40207

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4097

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 834772

Other (OTH) AF: 0.00 AC: 0 AN: 45656

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.239T>C (p.F80S) alteration is located in exon 2 (coding exon 2) of the TSPAN6 gene. This alteration results from a T to C substitution at nucleotide position 239, causing the phenylalanine (F) at amino acid position 80 to be replaced by a serine (S). 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	0.74
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.51	D
PhyloP100		7.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.82
Sift	Benign	0.044	D
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.69		Gain of glycosylation at F80 (P = 0.2669);
MVP		0.99
MPC		0.30
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.71
Mutation Taster		=35/65	disease causing

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

Other links and lift over

hg19: chrX-99890592;