X-100635658-T-C

Variant names:

• chrX-100635658-T-C
• rs374431442
• NM_003270.4:c.176A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003270.4(TSPAN6):​c.176A>G​(p.Asn59Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000501 in 1,197,769 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: TSPAN6 NM_003270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40127486).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003270.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN6	NM_003270.4	MANE Select	c.176A>G	p.Asn59Ser	missense	Exon 2 of 8	NP_003261.1	O43657
	TSPAN6	NM_001278740.2		c.-89A>G		5_prime_UTR	Exon 2 of 8	NP_001265669.1
	TSPAN6	NM_001278741.1		c.-89A>G		5_prime_UTR	Exon 2 of 8	NP_001265670.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN6	ENST00000373020.9	TSL:1 MANE Select	c.176A>G	p.Asn59Ser	missense	Exon 2 of 8	ENSP00000362111.4	O43657
	TSPAN6	ENST00000867886.1		c.176A>G	p.Asn59Ser	missense	Exon 2 of 7	ENSP00000537945.1
	TSPAN6	ENST00000867889.1		c.176A>G	p.Asn59Ser	missense	Exon 2 of 8	ENSP00000537948.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111879 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 4 AN: 1085890 Hom.: 0 Cov.: 30 AF XY: 0.00000567 AC XY: 2 AN XY: 352818

African (AFR) AF: 0.00 AC: 0 AN: 26270

American (AMR) AF: 0.00 AC: 0 AN: 34090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19161

East Asian (EAS) AF: 0.00 AC: 0 AN: 29974

South Asian (SAS) AF: 0.0000193 AC: 1 AN: 51909

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39941

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00000359 AC: 3 AN: 834688

Other (OTH) AF: 0.00 AC: 0 AN: 45736

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111879 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34053

African (AFR) AF: 0.0000650 AC: 2 AN: 30779

American (AMR) AF: 0.00 AC: 0 AN: 10551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.00 AC: 0 AN: 2650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6039

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53217

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.35
Sift	Benign	0.34	T
Sift4G	Benign	0.14	T
Polyphen		0.21	B
Vest4		0.56
MVP		0.29
MPC		0.060
ClinPred		0.84	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.63
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs374431442; hg19: chrX-99890655;