chr6-32067650-T-C

Variant names:

• chr6-32067650-T-C
• rs9469080
• NM_001365276.2:c.6544+11A>G

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.6544+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,611,500 control chromosomes in the GnomAD database, including 15,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2200 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12846 hom.)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.01
• Publications: 10 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=-0.97).
• BP6: Variant 6-32067650-T-C is Benign according to our data. Variant chr6-32067650-T-C is described in ClinVar as Benign. ClinVar VariationId is 261148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.6544+11A>G		intron_variant	Intron 18 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.7285+11A>G		intron_variant	Intron 19 of 44		NP_001415264.1
TNXB	NM_019105.8	c.6544+11A>G		intron_variant	Intron 18 of 43		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.6544+11A>G		intron_variant	Intron 18 of 43		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.7285+11A>G		intron_variant	Intron 19 of 44			ENSP00000497649.1
TNXB	ENST00000375244.7	c.6544+11A>G		intron_variant	Intron 18 of 43	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22593 AN: 152070 Hom.: 2189 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.0961

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.139 AC: 34197 AN: 245536 AF XY: 0.151

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0954

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.0657

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.111 AC: 162260 AN: 1459312 Hom.: 12846 Cov.: 32 AF XY: 0.119 AC XY: 86210 AN XY: 725614

African (AFR) AF: 0.257 AC: 8574 AN: 33390

American (AMR) AF: 0.102 AC: 4545 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2831 AN: 26008

East Asian (EAS) AF: 0.109 AC: 4329 AN: 39626

South Asian (SAS) AF: 0.343 AC: 29535 AN: 86140

European-Finnish (FIN) AF: 0.0686 AC: 3644 AN: 53118

Middle Eastern (MID) AF: 0.269 AC: 1539 AN: 5724

European-Non Finnish (NFE) AF: 0.0898 AC: 99767 AN: 1110526

Other (OTH) AF: 0.124 AC: 7496 AN: 60244

GnomAD4 genome AF: 0.149 AC: 22627 AN: 152188 Hom.: 2200 Cov.: 32 AF XY: 0.152 AC XY: 11293 AN XY: 74406

African (AFR) AF: 0.250 AC: 10359 AN: 41506

American (AMR) AF: 0.147 AC: 2250 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3470

East Asian (EAS) AF: 0.106 AC: 549 AN: 5184

South Asian (SAS) AF: 0.297 AC: 1429 AN: 4818

European-Finnish (FIN) AF: 0.0618 AC: 656 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.0961 AC: 6534 AN: 67994

Other (OTH) AF: 0.182 AC: 383 AN: 2110

Alfa AF: 0.122 Hom.: 465

Bravo AF: 0.155

Asia WGS AF: 0.247 AC: 859 AN: 3478

ClinVar

Significance: 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 10, 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	-0.97
CADD	Benign	2.1
DANN	Benign	0.43
PhyloP100		-3.0
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: rs9469080; hg19: chr6-32035427; COSMIC: COSV107499754;