rs587777683

Variant names:

• chr6-32048638-G-A
• rs587777683
• NM_001365276.2:c.9770C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_001365276.2(TNXB):​c.9770C>T​(p.Thr3257Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000525 in 1,334,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.25
• Publications: 4 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 6-32048638-G-A is Pathogenic according to our data. Variant chr6-32048638-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 144113.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.9770C>T	p.Thr3257Ile	missense_variant	Exon 29 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.10511C>T	p.Thr3504Ile	missense_variant	Exon 30 of 45		NP_001415264.1
TNXB	NM_019105.8	c.9764C>T	p.Thr3255Ile	missense_variant	Exon 29 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.9770C>T	p.Thr3257Ile	missense_variant	Exon 29 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.10511C>T	p.Thr3504Ile	missense_variant	Exon 30 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.9770C>T	p.Thr3257Ile	missense_variant	Exon 29 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000168 AC: 3 AN: 178724 AF XY: 0.0000307

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000525 AC: 7 AN: 1334512 Hom.: 0 Cov.: 32 AF XY: 0.00000766 AC XY: 5 AN XY: 652650

African (AFR) AF: 0.00 AC: 0 AN: 30360

American (AMR) AF: 0.00 AC: 0 AN: 32428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20176

East Asian (EAS) AF: 0.00 AC: 0 AN: 37858

South Asian (SAS) AF: 0.00 AC: 0 AN: 64244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4910

European-Non Finnish (NFE) AF: 0.00000670 AC: 7 AN: 1044720

Other (OTH) AF: 0.00 AC: 0 AN: 54660

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000837 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Vesicoureteral reflux 8 Pathogenic:2

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 27, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNXB c.9764C>T (p.Thr3255Ile) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 178724 control chromosomes (gnomAD). c.9764C>T has been reported in the literature in nine individuals affected with Vesicoureteral Reflux 8 in one family and this variant segregated with the disease (Gbadegesin_2013, Elahi_2015). Some of nine affected individuals also had joint hypermobility (Elahi_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and it showed that fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix (Gbadegesin_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23620400, 26408188). ClinVar contains an entry for this variant (Variation ID: 144113). To our knowledge, this variant has not been reported in individuals with autosomal recessive Ehlers-Danlos-like syndrome. Based on the evidence outlined above, this variant is likely pathogenic for autosomal dominant Vesicoureteral Reflux 8. -

not provided Uncertain:1

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	.;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.19	.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		2.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.7	.;.;D;.
REVEL	Uncertain	0.62
Sift	Benign	0.13	.;.;T;.
Sift4G	Pathogenic	0.0010	.;.;D;D
Vest4		0.69
MVP		0.17
ClinPred		0.44	T
GERP RS		3.1
Varity_R		0.17
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs587777683; hg19: chr6-32016415;