rs2856453

Variant names:

• chr6-32043458-C-A
• rs2856453
• NM_001365276.2:c.11629G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32043458-C-A
• chr6-32043458-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001365276.2(TNXB):​c.11629G>T​(p.Val3877Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3877I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 8)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 9 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23285097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11629G>T	p.Val3877Phe	missense_variant	Exon 36 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.12370G>T	p.Val4124Phe	missense_variant	Exon 37 of 45		NP_001415264.1
TNXB	NM_019105.8	c.11623G>T	p.Val3875Phe	missense_variant	Exon 36 of 44		NP_061978.6
TNXB	NM_032470.4	c.916G>T	p.Val306Phe	missense_variant	Exon 5 of 13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11629G>T	p.Val3877Phe	missense_variant	Exon 36 of 44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes Cov.: 8

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 509792 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 268720

African (AFR) AF: 0.00 AC: 0 AN: 14838

American (AMR) AF: 0.00 AC: 0 AN: 30558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15940

East Asian (EAS) AF: 0.00 AC: 0 AN: 31408

South Asian (SAS) AF: 0.00 AC: 0 AN: 52976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2176

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 303170

Other (OTH) AF: 0.00 AC: 0 AN: 28378

GnomAD4 genome Cov.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T;.;T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.0	.;T;T;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	.;.;.;.;.
PhyloP100		0.12
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.0	.;.;D;D;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;D;D;.
Sift4G	Pathogenic	0.0	.;.;D;D;D
Vest4		0.0
ClinPred		0.65	D
GERP RS		0.73
Varity_R		0.26
gMVP		0.54
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs2856453; hg19: chr6-32011235;