rs183760368

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001365276.2(TNXB):c.7856C>T(p.Pro2619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000873 in 1,612,584 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. P2619P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00079 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 0 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 2.67

Publications

1 publications found

Variant links:

Genes affected

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNXB Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome due to tenascin-X deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
familial vesicoureteral reflux
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
vesicoureteral reflux 8
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TNXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021029472).

BP6

Variant 6-32056873-G-A is Benign according to our data. Variant chr6-32056873-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521772.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.7856C>T	p.Pro2619Leu	missense_variant	Exon 23 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.8597C>T	p.Pro2866Leu	missense_variant	Exon 24 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.7856C>T	p.Pro2619Leu	missense_variant	Exon 23 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.7856C>T	p.Pro2619Leu	missense_variant	Exon 23 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.8597C>T	p.Pro2866Leu	missense_variant	Exon 24 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.7856C>T	p.Pro2619Leu	missense_variant	Exon 23 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000888

AC:

218

AN:

245398

AF XY:

0.000918

show subpopulations

Gnomad AFR exome

AF:

0.000274

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00171

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.000881

AC:

1286

AN:

1460318

Hom.:

Cov.:

AF XY:

0.000929

AC XY:

675

AN XY:

726420

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33466

American (AMR)

AF:

0.00110

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000684

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000763

AC:

AN:

52412

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000926

AC:

1029

AN:

1111554

Other (OTH)

AF:

0.00103

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

178

267

356

445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.000795

AC:

121

AN:

152266

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41538

American (AMR)

AF:

0.000784

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00107

Hom.:

Bravo

AF:

0.000842

ESP6500AA

AF:

0.000741

AC:

ESP6500EA

AF:

0.000580

AC:

ExAC

AF:

0.000873

AC:

105

EpiCase

AF:

0.00218

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency

Uncertain:3

Jun 26, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TNXB c.7856C>T (p.Pro2619Leu) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.001658 in the Ashkenazi Jewish population from the Genome Aggregation Database. Based on the limited evidence, the p.Pro2619Leu variant is classified as a variant of uncertain significance for Ehlers-Danlos syndrome due to tenascin-X deficiency. -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variant was identified, NM_001365276.1(TNXB):c.7856C>T in exon 23 of 44 of the TNXB gene (NB: this variant is non-coding in alternative transcripts). This substitution is predicted to create a moderate amino acid change from a proline to a leucine at position 2619 of the protein; NP_001352205.1(TNXB):p.(Pro2619Leu). The proline at this position has very low conservation (100 vertebrates, UCSC), and is not located within a particular domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.087% (241 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.12%. This variant has been previously reported as a VUS in a clinical case (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS. -

Sep 14, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNXB: BP4 -

Jun 20, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Sep 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Ehlers-Danlos syndrome

Uncertain:1

May 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 01, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TNXB c.7856C>T (p.Pro2619Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00087 in 1612584 control chromosomes, including 2 homozygotes, predominantly at a frequency of 0.0059 within the Middle Eastern subpopulation (gnomAD v4). The observed variant frequency within Middle Eastern control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNXB causing Ehlers-Danlos-like syndrome phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism. c.7856C>T has been reported in the literature in the heterozygous state in at least one individual affected with distal myopathy (e.g., Evila_2017), however without strong evidence for causality due to a co-occurring pathogenic TTN truncating variant. This report therefore does not provide unequivocal conclusions about association of the variant with Ehlers-Danlos-like syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 27796757). ClinVar contains an entry for this variant (Variation ID: 521772). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype

Benign:1

Feb 14, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.61

.;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

2.7

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.2

.;.;D;.

REVEL

Benign

0.19

Sift

Uncertain

0.0080

.;.;D;.

Sift4G

Uncertain

0.010

.;.;D;D

Vest4

0.099

MVP

0.26

ClinPred

0.096

GERP RS

4.1

Varity_R

0.13

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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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