rs3749962

Positions:

• chr6-32068580-G-A

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.6030C>T​(p.Pro2010=) 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

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=-0.82).
• BP6: Variant 6-32068580-G-A is Benign according to our data. Variant chr6-32068580-G-A is described in ClinVar as [Benign]. Clinvar id is 261144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32068580-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.6030C>T	p.Pro2010=	synonymous_variant	17/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.6030C>T	p.Pro2010=	synonymous_variant	17/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.6030C>T	p.Pro2010=	synonymous_variant	17/44		NM_001365276.2	ENSP00000496448
TNXB	ENST00000647633.1	c.6771C>T	p.Pro2257=	synonymous_variant	18/45			ENSP00000497649	P1
TNXB	ENST00000375244.7	c.6030C>T	p.Pro2010=	synonymous_variant	17/44	5		ENSP00000364393

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

GnomAD3 exomes AF: 0.139 AC: 34695 AN: 249064 Hom.: 3580 AF XY: 0.151 AC XY: 20381 AN XY: 135146

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 SAS exome AF: 0.351

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

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.343

Gnomad4 FIN exome AF: 0.0685

Gnomad4 NFE exome AF: 0.0901

Gnomad4 OTH exome AF: 0.125

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

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.0624

Gnomad4 NFE AF: 0.0964

Gnomad4 OTH AF: 0.182

Alfa AF: 0.117 Hom.: 641

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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 31, 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	-0.82
CADD	Benign	0.98
DANN	Benign	0.43

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: rs3749962; hg19: chr6-32036357; COSMIC: COSV64483711;