rs204878

Variant names:

• chr6-32077449-T-A
• rs204878
• NM_001365276.2:c.4375+1584A>T

Variant summary

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

The NM_001365276.2(TNXB):​c.4375+1584A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 152,346 control chromosomes in the GnomAD database, including 406 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 0.060 (406 hom., cov: 32)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.255
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.4375+1584A>T		intron_variant	Intron 11 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.5116+1584A>T		intron_variant	Intron 12 of 44		NP_001415264.1
TNXB	NM_019105.8	c.4375+1584A>T		intron_variant	Intron 11 of 43		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.4375+1584A>T		intron_variant	Intron 11 of 43		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9110 AN: 152228 Hom.: 406 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0432

Gnomad OTH AF: 0.0621

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

GnomAD4 genome AF: 0.0599 AC: 9124 AN: 152346 Hom.: 406 Cov.: 32 AF XY: 0.0561 AC XY: 4178 AN XY: 74494

African (AFR) AF: 0.119 AC: 4957 AN: 41560

American (AMR) AF: 0.0600 AC: 918 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5192

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10626

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0432 AC: 2938 AN: 68038

Other (OTH) AF: 0.0615 AC: 130 AN: 2114

Alfa AF: 0.0476 Hom.: 35

Bravo AF: 0.0687

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.82
DANN	Benign	0.41
PhyloP100		0.26
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: rs204878; hg19: chr6-32045226;