rs204885

Variant names:

• chr6-32062152-C-T
• rs204885
• NM_001365276.2:c.7168+5G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.7168+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0364 in 1,609,336 control chromosomes in the GnomAD database, including 1,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (189 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1150 hom.)
• Consequence: TNXB NM_001365276.2 splice_region, intron
• Scores: Splicing: ADA: 0.9956
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.37
• 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 6-32062152-C-T is Benign according to our data. Variant chr6-32062152-C-T is described in ClinVar as Benign. ClinVar VariationId is 261154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.7168+5G>A		splice_region_variant, intron_variant	Intron 20 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.7909+5G>A		splice_region_variant, intron_variant	Intron 21 of 44		NP_001415264.1
TNXB	NM_019105.8	c.7168+5G>A		splice_region_variant, intron_variant	Intron 20 of 43		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.7168+5G>A		splice_region_variant, intron_variant	Intron 20 of 43		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.7909+5G>A		splice_region_variant, intron_variant	Intron 21 of 44			ENSP00000497649.1
TNXB	ENST00000375244.7	c.7168+5G>A		splice_region_variant, intron_variant	Intron 20 of 43	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6579 AN: 152232 Hom.: 190 Cov.: 32

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0454

GnomAD2 exomes AF: 0.0251 AC: 6118 AN: 243866 AF XY: 0.0233

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00369

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0333

GnomAD4 exome AF: 0.0357 AC: 52050 AN: 1456986 Hom.: 1150 Cov.: 33 AF XY: 0.0338 AC XY: 24476 AN XY: 724008

African (AFR) AF: 0.0794 AC: 2652 AN: 33396

American (AMR) AF: 0.0356 AC: 1585 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 371 AN: 26040

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39600

South Asian (SAS) AF: 0.000291 AC: 25 AN: 86008

European-Finnish (FIN) AF: 0.00429 AC: 225 AN: 52456

Middle Eastern (MID) AF: 0.00765 AC: 44 AN: 5752

European-Non Finnish (NFE) AF: 0.0407 AC: 45108 AN: 1108974

Other (OTH) AF: 0.0338 AC: 2038 AN: 60214

GnomAD4 genome AF: 0.0432 AC: 6585 AN: 152350 Hom.: 189 Cov.: 32 AF XY: 0.0408 AC XY: 3042 AN XY: 74498

African (AFR) AF: 0.0805 AC: 3346 AN: 41572

American (AMR) AF: 0.0480 AC: 734 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00263 AC: 28 AN: 10630

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2295 AN: 68038

Other (OTH) AF: 0.0449 AC: 95 AN: 2116

Alfa AF: 0.0358 Hom.: 78

Bravo AF: 0.0497

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0335

EpiControl AF: 0.0332

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

- -

Ehlers-Danlos syndrome Benign:1

Jul 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

- -

Cardiovascular phenotype Benign:1

Dec 21, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.38
CADD	Benign	21
DANN	Benign	0.86
PhyloP100		4.4
PromoterAI		-0.23	Neutral
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.010		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: rs204885; hg19: chr6-32029929;