rs204883

Variant names:

• chr6-32064966-G-A
• rs204883
• NM_001365276.2:c.6696C>T

Your query was ambiguous. Multiple possible variants found:

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

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.6696C>T​(p.Asp2232Asp) 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
• Publications: 37 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=-0.86).
• BP6: Variant 6-32064966-G-A is Benign according to our data. Variant chr6-32064966-G-A is described in ClinVar as Benign. ClinVar VariationId is 261150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.6696C>T	p.Asp2232Asp	synonymous_variant	Exon 19 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.7437C>T	p.Asp2479Asp	synonymous_variant	Exon 20 of 45		NP_001415264.1
TNXB	NM_019105.8	c.6696C>T	p.Asp2232Asp	synonymous_variant	Exon 19 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.6696C>T	p.Asp2232Asp	synonymous_variant	Exon 19 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.7437C>T	p.Asp2479Asp	synonymous_variant	Exon 20 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.6696C>T	p.Asp2232Asp	synonymous_variant	Exon 19 of 44	5		ENSP00000364393.3

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

GnomAD2 exomes AF: 0.438 AC: 106625 AN: 243534 AF XY: 0.435

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 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

African (AFR) AF: 0.251 AC: 8391 AN: 33476

American (AMR) AF: 0.542 AC: 24176 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14548 AN: 26128

East Asian (EAS) AF: 0.451 AC: 17901 AN: 39686

South Asian (SAS) AF: 0.400 AC: 34527 AN: 86232

European-Finnish (FIN) AF: 0.461 AC: 24114 AN: 52280

Middle Eastern (MID) AF: 0.417 AC: 2398 AN: 5756

European-Non Finnish (NFE) AF: 0.395 AC: 439147 AN: 1111520

Other (OTH) AF: 0.400 AC: 24140 AN: 60350

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

African (AFR) AF: 0.249 AC: 10311 AN: 41486

American (AMR) AF: 0.459 AC: 7020 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1944 AN: 3468

East Asian (EAS) AF: 0.452 AC: 2324 AN: 5142

South Asian (SAS) AF: 0.417 AC: 2011 AN: 4828

European-Finnish (FIN) AF: 0.481 AC: 5085 AN: 10578

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.409 AC: 27804 AN: 67948

Other (OTH) AF: 0.368 AC: 775 AN: 2106

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vesicoureteral reflux 8 Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 04, 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	-0.86
CADD	Benign	0.069
DANN	Benign	0.67
PhyloP100		-4.3
Mutation Taster		=92/8	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: rs204883; hg19: chr6-32032743; COSMIC: COSV64487981; COSMIC: COSV64487981;