X-100636679-G-C

Variant names:

• chrX-100636679-G-C
• rs1171606806
• NM_003270.4:c.16C>G

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.16C>G​(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000458 in 1,090,897 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: TSPAN6 NM_003270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• 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=0.21095842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN6	NM_003270.4	c.16C>G	p.Arg6Gly	missense_variant	Exon 1 of 8	ENST00000373020.9	NP_003261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN6	ENST00000373020.9	c.16C>G	p.Arg6Gly	missense_variant	Exon 1 of 8	1	NM_003270.4	ENSP00000362111.4
TSPAN6	ENST00000496771.5	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 6	3
TSPAN6	ENST00000612152.4	c.-178+114C>G		intron_variant	Intron 1 of 6	5		ENSP00000482130.1
TSPAN6	ENST00000494424.1	n.359+114C>G		intron_variant	Intron 2 of 5	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1090897 Hom.: 0 Cov.: 29 AF XY: 0.00000280 AC XY: 1 AN XY: 356955

African (AFR) AF: 0.00 AC: 0 AN: 26218

American (AMR) AF: 0.00 AC: 0 AN: 34606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19275

East Asian (EAS) AF: 0.00 AC: 0 AN: 29881

South Asian (SAS) AF: 0.00 AC: 0 AN: 52246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40243

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00000596 AC: 5 AN: 838497

Other (OTH) AF: 0.00 AC: 0 AN: 45819

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16C>G (p.R6G) alteration is located in exon 1 (coding exon 1) of the TSPAN6 gene. This alteration results from a C to G substitution at nucleotide position 16, causing the arginine (R) at amino acid position 6 to be replaced by a glycine (G). 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.044	D
Polyphen		0.0030	B
Vest4		0.54
MutPred		0.26		Gain of glycosylation at S5 (P = 0.0492);
MVP		0.20
MPC		0.082
ClinPred		0.86	D
GERP RS		0.25
PromoterAI		-0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.70
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1171606806; hg19: chrX-99891676;