rs61740331

Positions:

• chr6-32049355-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.9672G>A​(p.Leu3224Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,612,520 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (154 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.95

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=-0.44).
• BP6: Variant 6-32049355-C-T is Benign according to our data. Variant chr6-32049355-C-T is described in ClinVar as [Benign]. Clinvar id is 261181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32049355-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.95 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.9672G>A	p.Leu3224Leu	synonymous_variant	28/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.9666G>A	p.Leu3222Leu	synonymous_variant	28/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.9672G>A	p.Leu3224Leu	synonymous_variant	28/44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.10413G>A	p.Leu3471Leu	synonymous_variant	29/45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.9672G>A	p.Leu3224Leu	synonymous_variant	28/44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1589 AN: 152210 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00703 AC: 1737 AN: 247136 Hom.: 13 AF XY: 0.00686 AC XY: 922 AN XY: 134386

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.00679

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00914

Gnomad OTH exome AF: 0.00747

GnomAD4 exome AF: 0.0116 AC: 16897 AN: 1460192 Hom.: 154 Cov.: 33 AF XY: 0.0111 AC XY: 8093 AN XY: 726426

Gnomad4 AFR exome AF: 0.0131

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.0225

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0104 AC: 1590 AN: 152328 Hom.: 9 Cov.: 33 AF XY: 0.00948 AC XY: 706 AN XY: 74488

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0114 Hom.: 5

Bravo AF: 0.0111

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TNXB: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	- -

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

Jul 16, 2022

- -

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	-0.44
CADD	Benign	2.0
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61740331; hg19: chr6-32017132;