rs115612382

Variant names:

• chr6-32069045-C-T
• rs115612382
• NM_001365276.2:c.5679G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365276.2(TNXB):​c.5679G>A​(p.Thr1893Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,612,742 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 32)
  • Exomes 𝑓: 0.011 (279 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.71
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-32069045-C-T is Benign according to our data. Variant chr6-32069045-C-T is described in ClinVar as Benign. ClinVar VariationId is 261142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.013 (1981/152228) while in subpopulation AMR AF = 0.036 (551/15286). AF 95% confidence interval is 0.0336. There are 36 homozygotes in GnomAd4. There are 891 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.5679G>A	p.Thr1893Thr	synonymous	Exon 16 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.6420G>A	p.Thr2140Thr	synonymous	Exon 17 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.5679G>A	p.Thr1893Thr	synonymous	Exon 16 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.5679G>A	p.Thr1893Thr	synonymous	Exon 16 of 44	ENSP00000496448.1
	TNXB	ENST00000647633.1		c.6420G>A	p.Thr2140Thr	synonymous	Exon 17 of 45	ENSP00000497649.1
	TNXB	ENST00000375244.7	TSL:5	c.5679G>A	p.Thr1893Thr	synonymous	Exon 16 of 44	ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 152110 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0160 AC: 3901 AN: 244238 AF XY: 0.0144

Gnomad AFR exome AF: 0.00649

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0302

GnomAD4 exome AF: 0.0113 AC: 16446 AN: 1460514 Hom.: 279 Cov.: 34 AF XY: 0.0111 AC XY: 8035 AN XY: 726550

African (AFR) AF: 0.00714 AC: 239 AN: 33480

American (AMR) AF: 0.0362 AC: 1620 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0969 AC: 2533 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00177 AC: 153 AN: 86254

European-Finnish (FIN) AF: 0.00147 AC: 77 AN: 52256

Middle Eastern (MID) AF: 0.0297 AC: 171 AN: 5766

European-Non Finnish (NFE) AF: 0.00944 AC: 10499 AN: 1111838

Other (OTH) AF: 0.0190 AC: 1148 AN: 60360

GnomAD4 genome AF: 0.0130 AC: 1981 AN: 152228 Hom.: 36 Cov.: 32 AF XY: 0.0120 AC XY: 891 AN XY: 74444

African (AFR) AF: 0.00617 AC: 256 AN: 41522

American (AMR) AF: 0.0360 AC: 551 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 349 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 725 AN: 68008

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0167 Hom.: 38

Bravo AF: 0.0168

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0162

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.055
DANN	Benign	0.40
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs115612382; hg19: chr6-32036822;