rs3749962

Variant names:

• chr6-32068580-G-A
• rs3749962
• NM_001365276.2:c.6030C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32068580-G-A
• chr6-32068580-G-T

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.6030C>T​(p.Pro2010Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,830 control chromosomes in the GnomAD database, including 15,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2202 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12905 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.11
• Publications: 20 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=-0.82).
• BP6: Variant 6-32068580-G-A is Benign according to our data. Variant chr6-32068580-G-A is described in ClinVar as Benign. ClinVar VariationId is 261144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.6030C>T	p.Pro2010Pro	synonymous_variant	Exon 17 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.6771C>T	p.Pro2257Pro	synonymous_variant	Exon 18 of 45		NP_001415264.1
TNXB	NM_019105.8	c.6030C>T	p.Pro2010Pro	synonymous_variant	Exon 17 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.6030C>T	p.Pro2010Pro	synonymous_variant	Exon 17 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.6771C>T	p.Pro2257Pro	synonymous_variant	Exon 18 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.6030C>T	p.Pro2010Pro	synonymous_variant	Exon 17 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22622 AN: 152080 Hom.: 2191 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.0624

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.0964

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.139 AC: 34695 AN: 249064 AF XY: 0.151

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0961

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.0659

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.111 AC: 162908 AN: 1461632 Hom.: 12905 Cov.: 35 AF XY: 0.119 AC XY: 86584 AN XY: 727096

African (AFR) AF: 0.257 AC: 8614 AN: 33480

American (AMR) AF: 0.103 AC: 4594 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2850 AN: 26136

East Asian (EAS) AF: 0.110 AC: 4350 AN: 39698

South Asian (SAS) AF: 0.343 AC: 29567 AN: 86256

European-Finnish (FIN) AF: 0.0685 AC: 3656 AN: 53360

Middle Eastern (MID) AF: 0.269 AC: 1549 AN: 5758

European-Non Finnish (NFE) AF: 0.0901 AC: 100188 AN: 1111850

Other (OTH) AF: 0.125 AC: 7540 AN: 60372

GnomAD4 genome AF: 0.149 AC: 22656 AN: 152198 Hom.: 2202 Cov.: 32 AF XY: 0.152 AC XY: 11315 AN XY: 74410

African (AFR) AF: 0.250 AC: 10361 AN: 41492

American (AMR) AF: 0.147 AC: 2251 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.106 AC: 547 AN: 5170

South Asian (SAS) AF: 0.296 AC: 1427 AN: 4818

European-Finnish (FIN) AF: 0.0624 AC: 662 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.0964 AC: 6557 AN: 68022

Other (OTH) AF: 0.182 AC: 384 AN: 2112

Alfa AF: 0.118 Hom.: 748

Bravo AF: 0.155

Asia WGS AF: 0.247 AC: 862 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.104

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

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 31, 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	-0.82
CADD	Benign	0.98
DANN	Benign	0.43
PhyloP100		-2.1
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: rs3749962; hg19: chr6-32036357; COSMIC: COSV64483711;