rs190967484

chr6-32072132-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001365276.2(TNXB):c.4848G>A(p.Gly1616=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,613,086 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.010 (116 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.688

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 6-32072132-C-T is Benign according to our data. Variant chr6-32072132-C-T is described in ClinVar as [Benign]. Clinvar id is 261139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32072132-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.688 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.4848G>A	p.Gly1616=	synonymous_variant	13/44	ENST00000644971.2
TNXB	NM_019105.8	c.4848G>A	p.Gly1616=	synonymous_variant	13/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.4848G>A	p.Gly1616=	synonymous_variant	13/44		NM_001365276.2
TNXB	ENST00000647633.1	c.5589G>A	p.Gly1863=	synonymous_variant	14/45			P1
TNXB	ENST00000375244.7	c.4848G>A	p.Gly1616=	synonymous_variant	13/44	5

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1534 AN: 152164 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.0101 AC: 2514 AN: 247782 Hom.: 24 AF XY: 0.0105 AC XY: 1415 AN XY: 134566

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.000390

Gnomad SAS exome AF: 0.00521

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0105 AC: 15295 AN: 1460804 Hom.: 116 Cov.: 31 AF XY: 0.0106 AC XY: 7684 AN XY: 726640

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00424

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00501

Gnomad4 FIN exome AF: 0.0255

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00883

GnomAD4 genome AF: 0.0101 AC: 1534 AN: 152282 Hom.: 16 Cov.: 32 AF XY: 0.0111 AC XY: 823 AN XY: 74452

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.0293

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0144 Hom.: 8

Bravo AF: 0.00755

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.00950

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TNXB: BP4, BP7, BS1, BS2 -

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

May 27, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 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	-0.42
Cadd	Benign	12
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs190967484; hg19: chr6-32039909; COSMIC: COSV64490030;