X-38675778-C-A

Position:

chrX-38675778-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004615.4(TSPAN7):c.515C>A(p.Pro172His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,209,067 control chromosomes in the GnomAD database, including 2 homozygotes. There are 648 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 31 hem., cov: 22)

Exomes 𝑓: 0.0017 ( 2 hom. 617 hem. )

Consequence

TSPAN7
NM_004615.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4

Conservation

PhyloP100: 1.71

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07774618).

BP6

Variant X-38675778-C-A is Benign according to our data. Variant chrX-38675778-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11630.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chrX-38675778-C-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 31 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN7	NM_004615.4 linkuse as main transcript	c.515C>A	p.Pro172His	missense_variant	5/8	ENST00000378482.7	NP_004606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN7	ENST00000378482.7 linkuse as main transcript	c.515C>A	p.Pro172His	missense_variant	5/8	1	NM_004615.4	ENSP00000367743	P1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

131

AN:

111068

Hom.:

Cov.:

AF XY:

0.000932

AC XY:

AN XY:

33264

show subpopulations

Gnomad AFR

AF:

0.000197

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000957

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000666

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00225

Gnomad OTH

AF:

0.000675

GnomAD3 exomes

AF:

0.000935

AC:

171

AN:

182969

Hom.:

AF XY:

0.000873

AC XY:

AN XY:

67565

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.000876

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00171

AC:

1874

AN:

1097999

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

617

AN XY:

363417

show subpopulations

Gnomad4 AFR exome

AF:

0.000189

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.000839

Gnomad4 NFE exome

AF:

0.00210

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00118

AC:

131

AN:

111068

Hom.:

Cov.:

AF XY:

0.000932

AC XY:

AN XY:

33264

show subpopulations

Gnomad4 AFR

AF:

0.000197

Gnomad4 AMR

AF:

0.0000957

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000666

Gnomad4 NFE

AF:

0.00225

Gnomad4 OTH

AF:

0.000675

Alfa

AF:

0.00218

Hom.:

Bravo

AF:

0.000918

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.00125

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 58

Pathogenic:1Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2018	- -

History of neurodevelopmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2012

In published studies involving a family with six affected males with non-syndromic X-linked mental retardation, this variant was present in all individuals with mental retardation and in one male whose IQ score is within the normal range (Zemni R et al. Nat Genet. 2000;24(2):167-170 and Gomot M et al. Am J Med Genet. 2002;112:400-404). In a separate study, this variant was observed in 1/105 males with mental retardation, and it was absent in this particular proband's unaffected brother (Maranduba CM et al. Am J Med Genet. 2004;124A:413-415). This variant has not been detected in conjunction with a pathogenic mutation to date.Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.05% (1/1997) in male alleles studied. The A-allele was observed in 0.07% (1/1475) of European American male alleles but was absent in 522 African American male alleles and was not observed in the homozygous state in 3381 female alleles studied (http://snp.gs.washington.edu/EVS). Furthermore, this variant was not detected in a total of 420 normal X chromosomes in all of the published studies. This amino acid position is not conserved on species alignment.This alteration is predicted to be benign with a score of 0.327 (sensitivity: 0.86; specificity: 0.76)This alteration is predicted to be tolerated with a score of 0.190 (conservation: 1.91) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

.;T;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.59

T;T;T

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.078

T;T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.4

.;L;.

MutationTaster

Benign

0.83

A;A;A;A

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.14

N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.083, 0.25

.;B;B

Vest4

0.32

MVP

0.37

MPC

0.69

ClinPred

0.023

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over