X-100635575-C-T

Position:

• chrX-100635575-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003270.4(TSPAN6):​c.259G>A​(p.Ala87Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,191,957 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 205 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., 19 hem., cov: 23)
  • Exomes 𝑓: 0.00051 (0 hom. 186 hem.)
• Consequence: TSPAN6 NM_003270.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013784647).
• BP6: Variant X-100635575-C-T is Benign according to our data. Variant chrX-100635575-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2661035.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN6	NM_003270.4	c.259G>A	p.Ala87Thr	missense_variant	2/8	ENST00000373020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN6	ENST00000373020.9	c.259G>A	p.Ala87Thr	missense_variant	2/8	1	NM_003270.4	P1
TSPAN6	ENST00000612152.4	c.-6G>A		5_prime_UTR_variant	2/7	5
TSPAN6	ENST00000494424.1	n.531G>A		non_coding_transcript_exon_variant	3/6	2
TSPAN6	ENST00000496771.5	n.671G>A		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes AF: 0.000562 AC: 63 AN: 112068 Hom.: 0 Cov.: 23 AF XY: 0.000555 AC XY: 19 AN XY: 34250

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.00302

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000920

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000614 AC: 103 AN: 167729 Hom.: 0 AF XY: 0.000484 AC XY: 26 AN XY: 53723

Gnomad AFR exome AF: 0.0000804

Gnomad AMR exome AF: 0.000159

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.000388

Gnomad NFE exome AF: 0.000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000506 AC: 546 AN: 1079836 Hom.: 0 Cov.: 30 AF XY: 0.000534 AC XY: 186 AN XY: 348290

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.000296

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000396

Gnomad4 FIN exome AF: 0.000399

Gnomad4 NFE exome AF: 0.000502

Gnomad4 OTH exome AF: 0.000507

GnomAD4 genome AF: 0.000562 AC: 63 AN: 112121 Hom.: 0 Cov.: 23 AF XY: 0.000554 AC XY: 19 AN XY: 34313

Gnomad4 AFR AF: 0.0000647

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00302

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000331

Gnomad4 NFE AF: 0.000920

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00112 Hom.: 45

Bravo AF: 0.000536

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000569 AC: 69

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

TSPAN6: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.2	N
MutationTaster	Benign	0.62	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.25
Sift	Benign	0.34	T
Sift4G	Benign	0.83	T
Polyphen		0.0030	B
Vest4		0.041
MVP		0.62
MPC		0.051
ClinPred		0.022	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs145821935; hg19: chrX-99890572;