rs397948

Positions:

• chr6-32043937-A-G
• chr6-32043937-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.11387-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 148,600 control chromosomes in the GnomAD database, including 17,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17379 hom., cov: 25)
  • Exomes 𝑓: 0.39 (118367 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.719

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 (BayesDel_noAF=-0.91).
• BP6: Variant 6-32043937-A-G is Benign according to our data. Variant chr6-32043937-A-G is described in ClinVar as [Benign]. Clinvar id is 261106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32043937-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11387-45T>C		intron_variant		ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.11381-45T>C		intron_variant			NP_061978.6
TNXB	NM_032470.4	c.674-45T>C		intron_variant			NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11387-45T>C		intron_variant			NM_001365276.2	ENSP00000496448

Frequencies

GnomAD3 genomes AF: 0.465 AC: 69081 AN: 148482 Hom.: 17351 Cov.: 25

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.470

GnomAD3 exomes AF: 0.413 AC: 100760 AN: 244178 Hom.: 23062 AF XY: 0.420 AC XY: 55682 AN XY: 132706

Gnomad AFR exome AF: 0.679

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.527

Gnomad SAS exome AF: 0.583

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.393

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.393 AC: 560814 AN: 1426856 Hom.: 118367 Cov.: 44 AF XY: 0.397 AC XY: 281530 AN XY: 709980

Gnomad4 AFR exome AF: 0.688

Gnomad4 AMR exome AF: 0.347

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.438

Gnomad4 SAS exome AF: 0.575

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.410

GnomAD4 genome AF: 0.465 AC: 69157 AN: 148600 Hom.: 17379 Cov.: 25 AF XY: 0.467 AC XY: 33855 AN XY: 72502

Gnomad4 AFR AF: 0.677

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.562

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.471

Alfa AF: 0.378 Hom.: 1948

Bravo AF: 0.474

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.096
DANN	Benign	0.20

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: rs397948; hg19: chr6-32011714; COSMIC: COSV64481248; COSMIC: COSV64481248;