rs17201560

Variant names:

• chr6-32079491-T-C
• rs17201560
• NM_001365276.2:c.4043-126A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001365276.2(TNXB):​c.4043-126A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 805,102 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (80 hom., cov: 32)
  • Exomes 𝑓: 0.036 (470 hom.)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.757
• Publications: 16 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)

ENSG00000294466 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0293 (4466/152264) while in subpopulation NFE AF = 0.0411 (2798/68004). AF 95% confidence interval is 0.0399. There are 80 homozygotes in GnomAd4. There are 2140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 80 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.4043-126A>G		intron_variant	Intron 10 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.4784-126A>G		intron_variant	Intron 11 of 44		NP_001415264.1
TNXB	NM_019105.8	c.4043-126A>G		intron_variant	Intron 10 of 43		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.4043-126A>G		intron_variant	Intron 10 of 43		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4460 AN: 152146 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0249

GnomAD4 exome AF: 0.0357 AC: 23302 AN: 652838 Hom.: 470 AF XY: 0.0355 AC XY: 11797 AN XY: 332380

African (AFR) AF: 0.0150 AC: 243 AN: 16182

American (AMR) AF: 0.0225 AC: 424 AN: 18878

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 285 AN: 14926

East Asian (EAS) AF: 0.0191 AC: 611 AN: 31994

South Asian (SAS) AF: 0.0265 AC: 1264 AN: 47628

European-Finnish (FIN) AF: 0.0330 AC: 1109 AN: 33604

Middle Eastern (MID) AF: 0.0190 AC: 74 AN: 3902

European-Non Finnish (NFE) AF: 0.0403 AC: 18266 AN: 452932

Other (OTH) AF: 0.0313 AC: 1026 AN: 32792

GnomAD4 genome AF: 0.0293 AC: 4466 AN: 152264 Hom.: 80 Cov.: 32 AF XY: 0.0287 AC XY: 2140 AN XY: 74456

African (AFR) AF: 0.0152 AC: 633 AN: 41564

American (AMR) AF: 0.0235 AC: 359 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5174

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4816

European-Finnish (FIN) AF: 0.0304 AC: 323 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2798 AN: 68004

Other (OTH) AF: 0.0246 AC: 52 AN: 2110

Alfa AF: 0.0334 Hom.: 131

Bravo AF: 0.0267

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.18
DANN	Benign	0.51
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism

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: rs17201560; hg19: chr6-32047268; COSMIC: COSV64480284; COSMIC: COSV64480284;