rs104894951

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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). Synonymous variant affecting the same amino acid position (i.e. P172P) has been classified as Benign.

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 U:3B:4

Conservation

PhyloP100: 1.71

Publications

16 publications found

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 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

TSPAN7 links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 11630.

BS2

High Hemizygotes in GnomAd4 at 31 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN7	NM_004615.4 link	c.515C>A	p.Pro172His	missense_variant	Exon 5 of 8	ENST00000378482.7	NP_004606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN7	ENST00000378482.7 link	c.515C>A	p.Pro172His	missense_variant	Exon 5 of 8	1	NM_004615.4	ENSP00000367743.2
ENSG00000250349	ENST00000465127.1 link	c.605C>A	p.Pro202His	missense_variant	Exon 7 of 9	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

131

AN:

111068

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000935

AC:

171

AN:

182969

AF XY:

0.000873

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 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

African (AFR)

AF:

0.000189

AC:

AN:

26396

American (AMR)

AF:

0.000227

AC:

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30167

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54138

European-Finnish (FIN)

AF:

0.000839

AC:

AN:

40513

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00210

AC:

1766

AN:

841992

Other (OTH)

AF:

0.00124

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00118

AC:

131

AN:

111068

Hom.:

Cov.:

AF XY:

0.000932

AC XY:

AN XY:

33264

show subpopulations

African (AFR)

AF:

0.000197

AC:

AN:

30480

American (AMR)

AF:

0.0000957

AC:

AN:

10447

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3514

South Asian (SAS)

AF:

0.00

AC:

AN:

2581

European-Finnish (FIN)

AF:

0.000666

AC:

AN:

6005

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.00225

AC:

119

AN:

52999

Other (OTH)

AF:

0.000675

AC:

AN:

1481

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00202

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: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 58

Uncertain:2Benign:1

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2004

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

History of neurodevelopmental disorder

Uncertain:1

Oct 12, 2012

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

1.7

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over