NM_001365276.2:c.3380A>C

Variant names:

• chr6-32084478-T-G
• rs61910712
• NM_001365276.2:c.3380A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365276.2(TNXB):​c.3380A>C​(p.Lys1127Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. K1127R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• 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)

ENSG00000294466 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3872156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.3380A>C	p.Lys1127Thr	missense_variant	Exon 8 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.4121A>C	p.Lys1374Thr	missense_variant	Exon 9 of 45		NP_001415264.1
TNXB	NM_019105.8	c.3380A>C	p.Lys1127Thr	missense_variant	Exon 8 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.3380A>C	p.Lys1127Thr	missense_variant	Exon 8 of 44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456002 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724026

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110188

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;.;T;.
Eigen	Benign	0.026
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.96	T
PhyloP100		2.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	.;.;D;.
REVEL	Benign	0.28
Sift	Benign	0.11	.;.;T;.
Sift4G	Uncertain	0.0030	.;.;D;D
Vest4		0.51
MutPred		0.51		Loss of methylation at K1127 (P = 0.0036);.;Loss of methylation at K1127 (P = 0.0036);.;
MVP		0.31
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.22
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61910712; hg19: chr6-32052255;