rs204883

Positions:

• chr6-32064966-G-A
• chr6-32064966-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365276.2(TNXB):​c.6696C>T​(p.Asp2232=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,612,086 control chromosomes in the GnomAD database, including 133,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11883 hom., cov: 31)
  • Exomes 𝑓: 0.40 (122050 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.29

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-32064966-G-A is Benign according to our data. Variant chr6-32064966-G-A is described in ClinVar as [Benign]. Clinvar id is 261150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32064966-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.6696C>T	p.Asp2232=	synonymous_variant	19/44	ENST00000644971.2
TNXB	NM_019105.8	c.6696C>T	p.Asp2232=	synonymous_variant	19/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.6696C>T	p.Asp2232=	synonymous_variant	19/44		NM_001365276.2
TNXB	ENST00000647633.1	c.7437C>T	p.Asp2479=	synonymous_variant	20/45			P1
TNXB	ENST00000375244.7	c.6696C>T	p.Asp2232=	synonymous_variant	19/44	5

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57919 AN: 151920 Hom.: 11874 Cov.: 31

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.368

GnomAD3 exomes AF: 0.438 AC: 106625 AN: 243534 Hom.: 24451 AF XY: 0.435 AC XY: 58028 AN XY: 133270

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.567

Gnomad EAS exome AF: 0.451

Gnomad SAS exome AF: 0.398

Gnomad FIN exome AF: 0.473

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.404 AC: 589342 AN: 1460048 Hom.: 122050 Cov.: 69 AF XY: 0.405 AC XY: 294009 AN XY: 726294

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.451

Gnomad4 SAS exome AF: 0.400

Gnomad4 FIN exome AF: 0.461

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.381 AC: 57948 AN: 152038 Hom.: 11883 Cov.: 31 AF XY: 0.387 AC XY: 28749 AN XY: 74314

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.368

Alfa AF: 0.400 Hom.: 5470

Bravo AF: 0.378

Asia WGS AF: 0.380 AC: 1323 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Vesicoureteral reflux 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

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	-0.86
CADD	Benign	0.069
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs204883; hg19: chr6-32032743; COSMIC: COSV64487981; COSMIC: COSV64487981;