rs149492184

Variant names:

• chr6-32052940-G-A
• rs149492184
• NM_001365276.2:c.8845C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32052940-G-A
• chr6-32052940-G-C
• chr6-32052940-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365276.2(TNXB):​c.8845C>T​(p.Pro2949Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2949T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.12
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1303924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.8845C>T	p.Pro2949Ser	missense_variant	Exon 26 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.9586C>T	p.Pro3196Ser	missense_variant	Exon 27 of 45		NP_001415264.1
TNXB	NM_019105.8	c.8839C>T	p.Pro2947Ser	missense_variant	Exon 26 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.8845C>T	p.Pro2949Ser	missense_variant	Exon 26 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.9586C>T	p.Pro3196Ser	missense_variant	Exon 27 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.8845C>T	p.Pro2949Ser	missense_variant	Exon 26 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TNXB-related disorder Uncertain:1

Oct 14, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNXB c.8839C>T variant is predicted to result in the amino acid substitution p.Pro2947Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	.;.;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.12	.;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.92	T
PhyloP100		-1.1
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.2	.;.;D;.
REVEL	Benign	0.028
Sift	Benign	0.086	.;.;T;.
Sift4G	Benign	0.13	.;.;T;T
Vest4		0.048
MVP		0.043
ClinPred		0.82	D
GERP RS		1.5
Varity_R		0.046
Mutation Taster		=100/0	polymorphism

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: rs149492184; hg19: chr6-32020717; COSMIC: COSV64485300;