rs369637

Variant names:

• chr6-32058086-C-T
• rs369637
• NM_001365276.2:c.7797G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365276.2(TNXB):​c.7797G>A​(p.Leu2599Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,610,946 control chromosomes in the GnomAD database, including 17,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (937 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16286 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.21
• Publications: 17 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=-0.52).
• BP6: Variant 6-32058086-C-T is Benign according to our data. Variant chr6-32058086-C-T is described in ClinVar as Benign. ClinVar VariationId is 261165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.7797G>A	p.Leu2599Leu	synonymous_variant	Exon 22 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.8538G>A	p.Leu2846Leu	synonymous_variant	Exon 23 of 45		NP_001415264.1
TNXB	NM_019105.8	c.7797G>A	p.Leu2599Leu	synonymous_variant	Exon 22 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.7797G>A	p.Leu2599Leu	synonymous_variant	Exon 22 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.8538G>A	p.Leu2846Leu	synonymous_variant	Exon 23 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.7797G>A	p.Leu2599Leu	synonymous_variant	Exon 22 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15040 AN: 152140 Hom.: 935 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.0780

GnomAD2 exomes AF: 0.0908 AC: 22249 AN: 244988 AF XY: 0.0898

Gnomad AFR exome AF: 0.0535

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.0531

Gnomad EAS exome AF: 0.0144

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.0918

GnomAD4 exome AF: 0.139 AC: 202166 AN: 1458688 Hom.: 16286 Cov.: 31 AF XY: 0.135 AC XY: 97956 AN XY: 725390

African (AFR) AF: 0.0577 AC: 1929 AN: 33432

American (AMR) AF: 0.0433 AC: 1930 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 1505 AN: 26062

East Asian (EAS) AF: 0.0185 AC: 735 AN: 39640

South Asian (SAS) AF: 0.0268 AC: 2308 AN: 86176

European-Finnish (FIN) AF: 0.115 AC: 5990 AN: 52268

Middle Eastern (MID) AF: 0.0304 AC: 173 AN: 5684

European-Non Finnish (NFE) AF: 0.162 AC: 180357 AN: 1110592

Other (OTH) AF: 0.120 AC: 7239 AN: 60238

GnomAD4 genome AF: 0.0988 AC: 15046 AN: 152258 Hom.: 937 Cov.: 32 AF XY: 0.0935 AC XY: 6961 AN XY: 74444

African (AFR) AF: 0.0558 AC: 2321 AN: 41560

American (AMR) AF: 0.0561 AC: 859 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3468

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5172

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4832

European-Finnish (FIN) AF: 0.110 AC: 1173 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10026 AN: 67982

Other (OTH) AF: 0.0772 AC: 163 AN: 2112

Alfa AF: 0.123 Hom.: 570

Bravo AF: 0.0917

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.124

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.5
DANN	Benign	0.55
PhyloP100		-1.2
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: rs369637; hg19: chr6-32025863; COSMIC: COSV64479032;