chrX-38666265-G-T

Variant names:

• chrX-38666265-G-T
• rs2147449772
• NM_004615.4:c.226G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004615.4(TSPAN7):​c.226G>T​(p.Gly76*) 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 Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TSPAN7 NM_004615.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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 10 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN7	NM_004615.4	MANE Select	c.226G>T	p.Gly76*	stop_gained	Exon 2 of 8	NP_004606.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN7	ENST00000378482.7	TSL:1 MANE Select	c.226G>T	p.Gly76*	stop_gained	Exon 2 of 8	ENSP00000367743.2	P41732
	ENSG00000250349	ENST00000465127.1	TSL:5	c.316G>T	p.Gly106*	stop_gained	Exon 4 of 9	ENSP00000417050.1	B4E171
	TSPAN7	ENST00000286824.6	TSL:2	c.277G>T	p.Gly93*	stop_gained	Exon 3 of 9	ENSP00000286824.6	B4DDG0

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.6
Vest4		0.59
GERP RS		6.0
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2147449772; hg19: chrX-38525519;