X-38681258-G-T

Variant names:

• chrX-38681258-G-T
• rs104894950
• NM_004615.4:c.652G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004615.4(TSPAN7):​c.652G>T​(p.Gly218*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TSPAN7 NM_004615.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.25
• Publications: 2 publications found

Genes affected

TSPAN7 (HGNC:11854): (tetraspanin 7) 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. This encoded protein is a cell surface glycoprotein and may have a role in the control of neurite outgrowth. It is known to complex with integrins. This gene is associated with X-linked cognitive disability and neuropsychiatric diseases such as Huntington's chorea, fragile X syndrome and myotonic dystrophy. [provided by RefSeq, Jul 2008]

TSPAN7 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 58

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38681258-G-T is Pathogenic according to our data. Variant chrX-38681258-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11629.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004615.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN7	NM_004615.4	MANE Select	c.652G>T	p.Gly218*	stop_gained	Exon 6 of 8	NP_004606.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN7	ENST00000378482.7	TSL:1 MANE Select	c.652G>T	p.Gly218*	stop_gained	Exon 6 of 8	ENSP00000367743.2
	ENSG00000250349	ENST00000465127.1	TSL:5	c.742G>T	p.Gly248*	stop_gained	Exon 8 of 9	ENSP00000417050.1
	TSPAN7	ENST00000286824.6	TSL:2	c.703G>T	p.Gly235*	stop_gained	Exon 7 of 9	ENSP00000286824.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 58 Pathogenic:1

Feb 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.2
Vest4		0.45
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: 29

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104894950; hg19: chrX-38540512;