rs397948

Variant names:

• chr6-32043937-A-G
• rs397948
• NM_001365276.2:c.11387-45T>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

TNXB Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11387-45T>C		intron_variant	Intron 34 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.12128-45T>C		intron_variant	Intron 35 of 44		NP_001415264.1
TNXB	NM_019105.8	c.11381-45T>C		intron_variant	Intron 34 of 43		NP_061978.6
TNXB	NM_032470.4	c.674-45T>C		intron_variant	Intron 3 of 12		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11387-45T>C		intron_variant	Intron 34 of 43		NM_001365276.2	ENSP00000496448.1

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

GnomAD2 exomes AF: 0.413 AC: 100760 AN: 244178 AF XY: 0.420

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.688 AC: 22589 AN: 32844

American (AMR) AF: 0.347 AC: 15436 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7061 AN: 25822

East Asian (EAS) AF: 0.438 AC: 17259 AN: 39428

South Asian (SAS) AF: 0.575 AC: 48855 AN: 85010

European-Finnish (FIN) AF: 0.375 AC: 19202 AN: 51210

Middle Eastern (MID) AF: 0.442 AC: 2502 AN: 5666

European-Non Finnish (NFE) AF: 0.373 AC: 403661 AN: 1083238

Other (OTH) AF: 0.410 AC: 24249 AN: 59216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.677 AC: 27278 AN: 40272

American (AMR) AF: 0.385 AC: 5780 AN: 15018

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 914 AN: 3438

East Asian (EAS) AF: 0.516 AC: 2557 AN: 4958

South Asian (SAS) AF: 0.562 AC: 2590 AN: 4612

European-Finnish (FIN) AF: 0.389 AC: 4001 AN: 10274

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.368 AC: 24568 AN: 66766

Other (OTH) AF: 0.471 AC: 975 AN: 2072

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vesicoureteral reflux 8 Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.096
DANN	Benign	0.20
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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