rs369637

chr6-32058086-C-T

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.7797G>A(p.Leu2599=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,610,946 control chromosomes in the GnomAD database, including 17,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (937 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16286 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.21

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=-0.52).
• BP6: Variant 6-32058086-C-T is Benign according to our data. Variant chr6-32058086-C-T is described in ClinVar as [Benign]. Clinvar id is 261165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32058086-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.7797G>A	p.Leu2599=	synonymous_variant	22/44	ENST00000644971.2
TNXB	NM_019105.8	c.7797G>A	p.Leu2599=	synonymous_variant	22/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.7797G>A	p.Leu2599=	synonymous_variant	22/44		NM_001365276.2
TNXB	ENST00000647633.1	c.8538G>A	p.Leu2846=	synonymous_variant	23/45			P1
TNXB	ENST00000375244.7	c.7797G>A	p.Leu2599=	synonymous_variant	22/44	5

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15040 AN: 152140 Hom.: 935 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.0780

GnomAD3 exomes AF: 0.0908 AC: 22249 AN: 244988 Hom.: 1419 AF XY: 0.0898 AC XY: 11996 AN XY: 133562

Gnomad AFR exome AF: 0.0535

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.0531

Gnomad EAS exome AF: 0.0144

Gnomad SAS exome AF: 0.0293

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.0918

GnomAD4 exome AF: 0.139 AC: 202166 AN: 1458688 Hom.: 16286 Cov.: 31 AF XY: 0.135 AC XY: 97956 AN XY: 725390

Gnomad4 AFR exome AF: 0.0577

Gnomad4 AMR exome AF: 0.0433

Gnomad4 ASJ exome AF: 0.0577

Gnomad4 EAS exome AF: 0.0185

Gnomad4 SAS exome AF: 0.0268

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.0988 AC: 15046 AN: 152258 Hom.: 937 Cov.: 32 AF XY: 0.0935 AC XY: 6961 AN XY: 74444

Gnomad4 AFR AF: 0.0558

Gnomad4 AMR AF: 0.0561

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.0273

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.0772

Alfa AF: 0.123 Hom.: 570

Bravo AF: 0.0917

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.124

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

Sep 20, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 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	-0.52
Cadd	Benign	2.5
Dann	Benign	0.55

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: rs369637; hg19: chr6-32025863; COSMIC: COSV64479032;