rs17207902

chr6-32061592-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365276.2(TNXB):c.7297G>A(p.Val2433Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,613,170 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V2433V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.537

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051888227).
• BP6: Variant 6-32061592-C-T is Benign according to our data. Variant chr6-32061592-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00569 (866/152206) while in subpopulation AFR AF= 0.0163 (678/41512). AF 95% confidence interval is 0.0153. There are 7 homozygotes in gnomad4. There are 395 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.7297G>A	p.Val2433Ile	missense_variant	21/44	ENST00000644971.2
TNXB	NM_019105.8	c.7297G>A	p.Val2433Ile	missense_variant	21/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.7297G>A	p.Val2433Ile	missense_variant	21/44		NM_001365276.2
TNXB	ENST00000647633.1	c.8038G>A	p.Val2680Ile	missense_variant	22/45			P1
TNXB	ENST00000375244.7	c.7297G>A	p.Val2433Ile	missense_variant	21/44	5

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 861 AN: 152088 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00219 AC: 537 AN: 245738 Hom.: 5 AF XY: 0.00197 AC XY: 264 AN XY: 133990

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00223 AC: 3265 AN: 1460964 Hom.: 12 Cov.: 122 AF XY: 0.00217 AC XY: 1579 AN XY: 726764

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00569 AC: 866 AN: 152206 Hom.: 7 Cov.: 32 AF XY: 0.00531 AC XY: 395 AN XY: 74418

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00228 Hom.: 1

Bravo AF: 0.00660

ESP6500AA AF: 0.0186 AC: 42

ESP6500EA AF: 0.00162 AC: 8

ExAC AF: 0.00252 AC: 302

EpiCase AF: 0.00158

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 10, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 04, 2020

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency;C4014831:Vesicoureteral reflux 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	11
Dann	Benign	0.95
DEOGEN2	Benign	0.028	T;.;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.032	N
MetaRNN	Benign	0.0052	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
Vest4		0.10
MVP		0.068
ClinPred		0.0013	T
GERP RS		1.1
Varity_R		0.054

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: rs17207902; hg19: chr6-32029369;