6-32044149-C-T

Variant names:

• chr6-32044149-C-T
• rs77466839
• NM_001365276.2:c.11264-20G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365276.2(TNXB):​c.11264-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,471,384 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (56 hom., cov: 19)
  • Exomes 𝑓: 0.019 (492 hom.)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64
• Publications: 0 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=-0.86).
• BP6: Variant 6-32044149-C-T is Benign according to our data. Variant chr6-32044149-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 261104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2150/132592) while in subpopulation NFE AF = 0.0235 (1443/61452). AF 95% confidence interval is 0.0225. There are 56 homozygotes in GnomAd4. There are 1059 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11264-20G>A		intron_variant	Intron 33 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.12005-20G>A		intron_variant	Intron 34 of 44		NP_001415264.1
TNXB	NM_019105.8	c.11258-20G>A		intron_variant	Intron 33 of 43		NP_061978.6
TNXB	NM_032470.4	c.551-20G>A		intron_variant	Intron 2 of 12		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11264-20G>A		intron_variant	Intron 33 of 43		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2155 AN: 132510 Hom.: 57 Cov.: 19

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.0151

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.0194

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0304

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0185 AC: 3726 AN: 201420 AF XY: 0.0187

Gnomad AFR exome AF: 0.00287

Gnomad AMR exome AF: 0.00922

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.0216

Gnomad FIN exome AF: 0.0295

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0192 AC: 25760 AN: 1338792 Hom.: 492 Cov.: 31 AF XY: 0.0192 AC XY: 12779 AN XY: 665472

African (AFR) AF: 0.00261 AC: 80 AN: 30612

American (AMR) AF: 0.00919 AC: 363 AN: 39516

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 492 AN: 24928

East Asian (EAS) AF: 0.0123 AC: 461 AN: 37624

South Asian (SAS) AF: 0.0147 AC: 1142 AN: 77604

European-Finnish (FIN) AF: 0.0288 AC: 1397 AN: 48426

Middle Eastern (MID) AF: 0.0209 AC: 87 AN: 4162

European-Non Finnish (NFE) AF: 0.0204 AC: 20787 AN: 1020046

Other (OTH) AF: 0.0170 AC: 951 AN: 55874

GnomAD4 genome AF: 0.0162 AC: 2150 AN: 132592 Hom.: 56 Cov.: 19 AF XY: 0.0165 AC XY: 1059 AN XY: 64068

African (AFR) AF: 0.00317 AC: 109 AN: 34388

American (AMR) AF: 0.00529 AC: 70 AN: 13230

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 62 AN: 3204

East Asian (EAS) AF: 0.0195 AC: 89 AN: 4554

South Asian (SAS) AF: 0.0130 AC: 50 AN: 3856

European-Finnish (FIN) AF: 0.0315 AC: 284 AN: 9026

Middle Eastern (MID) AF: 0.0219 AC: 6 AN: 274

European-Non Finnish (NFE) AF: 0.0235 AC: 1443 AN: 61452

Other (OTH) AF: 0.0138 AC: 25 AN: 1814

Alfa AF: 0.0214 Hom.: 22

Bravo AF: 0.0141

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.020
DANN	Benign	0.56
PhyloP100		-1.6
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: rs77466839; hg19: chr6-32011926;