rs204887

chr6-32061449-A-Gchr6-32061449-A-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.7440T>C(p.Tyr2480=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,612,076 control chromosomes in the GnomAD database, including 379,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y2480*?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.64 (31805 hom., cov: 31)
  • Exomes 𝑓: 0.69 (347364 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.50

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=-0.75).
• BP6: Variant 6-32061449-A-G is Benign according to our data. Variant chr6-32061449-A-G is described in ClinVar as [Benign]. Clinvar id is 261159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32061449-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.7440T>C	p.Tyr2480=	synonymous_variant	21/44	ENST00000644971.2
TNXB	NM_019105.8	c.7440T>C	p.Tyr2480=	synonymous_variant	21/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.7440T>C	p.Tyr2480=	synonymous_variant	21/44		NM_001365276.2
TNXB	ENST00000647633.1	c.8181T>C	p.Tyr2727=	synonymous_variant	22/45			P1
TNXB	ENST00000375244.7	c.7440T>C	p.Tyr2480=	synonymous_variant	21/44	5

Frequencies

GnomAD3 genomes AF: 0.641 AC: 96871 AN: 151032 Hom.: 31788 Cov.: 31

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.646

GnomAD3 exomes AF: 0.691 AC: 170335 AN: 246578 Hom.: 59730 AF XY: 0.699 AC XY: 93815 AN XY: 134182

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.719

Gnomad ASJ exome AF: 0.739

Gnomad EAS exome AF: 0.617

Gnomad SAS exome AF: 0.784

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.694

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.687 AC: 1004151 AN: 1460928 Hom.: 347364 Cov.: 118 AF XY: 0.692 AC XY: 502599 AN XY: 726812

Gnomad4 AFR exome AF: 0.528

Gnomad4 AMR exome AF: 0.715

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.654

Gnomad4 SAS exome AF: 0.776

Gnomad4 FIN exome AF: 0.668

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.678

GnomAD4 genome AF: 0.641 AC: 96935 AN: 151148 Hom.: 31805 Cov.: 31 AF XY: 0.644 AC XY: 47616 AN XY: 73902

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.745

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.689

Gnomad4 OTH AF: 0.643

Alfa AF: 0.671 Hom.: 14880

Bravo AF: 0.632

Asia WGS AF: 0.689 AC: 2397 AN: 3478

EpiCase AF: 0.703

EpiControl AF: 0.702

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

-

- -

Vesicoureteral reflux 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 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	-0.75
Cadd	Benign	0.041
Dann	Benign	0.58

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: rs204887; hg19: chr6-32029226; COSMIC: COSV64481398; COSMIC: COSV64481398;