rs746016355

Positions:

• chr6-32070409-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001365276.2(TNXB):​c.4996C>T​(p.Arg1666*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,435,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TNXB NM_001365276.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.4996C>T	p.Arg1666*	stop_gained	14/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.4996C>T	p.Arg1666*	stop_gained	14/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.4996C>T	p.Arg1666*	stop_gained	14/44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.5737C>T	p.Arg1913*	stop_gained	15/45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.4996C>T	p.Arg1666*	stop_gained	14/44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000846 AC: 2 AN: 236470 Hom.: 0 AF XY: 0.0000154 AC XY: 2 AN XY: 129504

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 SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1435200 Hom.: 0 Cov.: 31 AF XY: 0.00000422 AC XY: 3 AN XY: 710340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 16, 2014

The p.Arg1666X variant in TNXB has not been previously reported in the literature but has been identified in 1/13218 South Asian chromosomes by the Exome Aggregation Consortium (ExAC) (http://exac.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1666, which is predicted to lead to a truncated or absent protein. Complete loss of TNXB function has been described in a few families with Ehlers-Danlos-like syndrome (Schalkwijk 2001, Merke 2013, Penisson-Besnier 2013) and a TNXB mouse knockout model indicates that complete loss of TNXB function results in abnormal collagen deposition (Mao 2002). In summary, while there is some suspicion for a pathogenic role of loss-of-function TNXB variants in Ehlers-Danlos-like syndrome, the clinical significance of the p.Arg1666X variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.045
FATHMM_MKL	Benign	0.11	N
Vest4		0.67
GERP RS		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs746016355; hg19: chr6-32038186; COSMIC: COSV64480631;