6-32051969-G-C

Variant names:

• chr6-32051969-G-C
• rs2857009
• NM_001365276.2:c.9115+701C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001365276.2(TNXB):​c.9115+701C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,076 control chromosomes in the GnomAD database, including 6,404 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 0.26 (6404 hom., cov: 31)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 32 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.9115+701C>G		intron_variant	Intron 26 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.9856+701C>G		intron_variant	Intron 27 of 44		NP_001415264.1
TNXB	NM_019105.8	c.9109+701C>G		intron_variant	Intron 26 of 43		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.9115+701C>G		intron_variant	Intron 26 of 43		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.9856+701C>G		intron_variant	Intron 27 of 44			ENSP00000497649.1
TNXB	ENST00000375244.7	c.9115+701C>G		intron_variant	Intron 26 of 43	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38968 AN: 151958 Hom.: 6396 Cov.: 31

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.256 AC: 38982 AN: 152076 Hom.: 6404 Cov.: 31 AF XY: 0.262 AC XY: 19486 AN XY: 74326

African (AFR) AF: 0.0595 AC: 2469 AN: 41512

American (AMR) AF: 0.376 AC: 5745 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1607 AN: 3468

East Asian (EAS) AF: 0.204 AC: 1055 AN: 5176

South Asian (SAS) AF: 0.243 AC: 1171 AN: 4818

European-Finnish (FIN) AF: 0.400 AC: 4218 AN: 10550

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21691 AN: 67964

Other (OTH) AF: 0.253 AC: 534 AN: 2108

Alfa AF: 0.294 Hom.: 965

Bravo AF: 0.248

Asia WGS AF: 0.225 AC: 784 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.68
DANN	Benign	0.57
PhyloP100		-1.0
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: rs2857009; hg19: chr6-32019746;