rs115612382

chr6-32069045-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365276.2(TNXB):c.5679G>A(p.Thr1893=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,612,742 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 32)
  • Exomes 𝑓: 0.011 (279 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.71

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=-0.74).
• BP6: Variant 6-32069045-C-T is Benign according to our data. Variant chr6-32069045-C-T is described in ClinVar as [Benign]. Clinvar id is 261142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32069045-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.013 (1981/152228) while in subpopulation AMR AF= 0.036 (551/15286). AF 95% confidence interval is 0.0336. There are 36 homozygotes in gnomad4. There are 891 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.5679G>A	p.Thr1893=	synonymous_variant	16/44	ENST00000644971.2
TNXB	NM_019105.8	c.5679G>A	p.Thr1893=	synonymous_variant	16/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.5679G>A	p.Thr1893=	synonymous_variant	16/44		NM_001365276.2
TNXB	ENST00000647633.1	c.6420G>A	p.Thr2140=	synonymous_variant	17/45			P1
TNXB	ENST00000375244.7	c.5679G>A	p.Thr1893=	synonymous_variant	16/44	5

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 152110 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0160 AC: 3901 AN: 244238 Hom.: 118 AF XY: 0.0144 AC XY: 1925 AN XY: 133670

Gnomad AFR exome AF: 0.00649

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00184

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0302

GnomAD4 exome AF: 0.0113 AC: 16446 AN: 1460514 Hom.: 279 Cov.: 34 AF XY: 0.0111 AC XY: 8035 AN XY: 726550

Gnomad4 AFR exome AF: 0.00714

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.0969

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00147

Gnomad4 NFE exome AF: 0.00944

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0130 AC: 1981 AN: 152228 Hom.: 36 Cov.: 32 AF XY: 0.0120 AC XY: 891 AN XY: 74444

Gnomad4 AFR AF: 0.00617

Gnomad4 AMR AF: 0.0360

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0167 Hom.: 38

Bravo AF: 0.0168

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

-

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 28, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2019

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	-0.74
Cadd	Benign	0.055
Dann	Benign	0.40

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: rs115612382; hg19: chr6-32036822;