chr6-32084536-C-T

Position:

chr6-32084536-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001365276.2(TNXB):c.3322G>A(p.Val1108Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,608,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:3

Conservation

PhyloP100: 0.652

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05631751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.3322G>A	p.Val1108Met	missense_variant	8/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.3322G>A	p.Val1108Met	missense_variant	8/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.3322G>A	p.Val1108Met	missense_variant	8/44		NM_001365276.2	ENSP00000496448		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.4063G>A	p.Val1355Met	missense_variant	9/45			ENSP00000497649	P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.3322G>A	p.Val1108Met	missense_variant	8/44	5		ENSP00000364393		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000827

AC:

202

AN:

244180

Hom.:

AF XY:

0.000778

AC XY:

104

AN XY:

133644

show subpopulations

Gnomad AFR exome

AF:

0.0000698

Gnomad AMR exome

AF:

0.000931

Gnomad ASJ exome

AF:

0.00955

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000583

Gnomad OTH exome

AF:

0.000835

GnomAD4 exome

AF:

0.000704

AC:

1025

AN:

1456536

Hom.:

Cov.:

AF XY:

0.000678

AC XY:

491

AN XY:

724360

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000703

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.000580

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000690

AC:

105

AN:

152256

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000986

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000979

AC:

ExAC

AF:

0.000685

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 22, 2022	This sequence change is predicted to replace valine with methionine at codon 1108 of the TNXB protein, p.(Val1108Met), also known as p.(Val1195Met). The valine residue is lowly conserved with methionine present in at least two vertebrates (100 vertebrates, UCSC), and is located in the fibronectin type-III 2 domain. There is a small physicochemical difference between valine and methionine. The variant is present in a large population cohort at a frequency of 0.08% (rs121912575, 221/275,544 alleles, 1 homozygote in gnomAD v2.1), with an allele frequency of 1% in the Ashkenazi Jewish population (98/10,232 alleles, 1 homozygote). The variant has been identified heterozygous (with no other TNXB variant detected) in a single hypermobility-type Ehlers-Danlos syndrome case with normal TNX serum levels and a significant increase in elastic fibre length in a skin biopsy (PMID: 15733269). It has also been identified in centenarians (PMID: 25333069). In molecular polypeptide analyses the variant does not alter three dimensional structure and demonstrates mild destabilization effects on the thermodynamic and mechanical stability (PMID: 20853426). The variant has previously been reported as a variant of uncertain significance (LOVD). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. No criteria are met. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2021	This variant is associated with the following publications: (PMID: 15733269, 25333069, 20853426, 27989960) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 25, 2023	BS1 -

Ehlers-Danlos syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2021

- -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 04, 2021

ACMG classification criteria: PS4 -

TNXB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2022

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

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.91

.;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.056

T;T;T;T

MetaSVM

Uncertain

-0.20

MutationTaster

Benign

0.11

A;A

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.7

.;.;N;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0080

.;.;D;.

Sift4G

Uncertain

0.0040

.;.;D;D

Vest4

0.76

MVP

0.73

ClinPred

0.086

GERP RS

4.1

Varity_R

0.13

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