rs12198173

Variant names:

• chr6-32059031-G-A
• rs12198173
• NM_001365276.2:c.7493-641C>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.7493-641C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 151,826 control chromosomes in the GnomAD database, including 1,067 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 0.10 (1067 hom., cov: 31)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200
• Publications: 55 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.7493-641C>T		intron_variant	Intron 21 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.8234-641C>T		intron_variant	Intron 22 of 44		NP_001415264.1
TNXB	NM_019105.8	c.7493-641C>T		intron_variant	Intron 21 of 43		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.7493-641C>T		intron_variant	Intron 21 of 43		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.8234-641C>T		intron_variant	Intron 22 of 44			ENSP00000497649.1
TNXB	ENST00000375244.7	c.7493-641C>T		intron_variant	Intron 21 of 43	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15475 AN: 151708 Hom.: 1071 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0528

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.0358

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0537

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0881

Gnomad OTH AF: 0.0960

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

GnomAD4 genome AF: 0.102 AC: 15488 AN: 151826 Hom.: 1067 Cov.: 31 AF XY: 0.100 AC XY: 7438 AN XY: 74230

African (AFR) AF: 0.158 AC: 6497 AN: 41138

American (AMR) AF: 0.0526 AC: 804 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3470

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5186

South Asian (SAS) AF: 0.151 AC: 730 AN: 4828

European-Finnish (FIN) AF: 0.0537 AC: 569 AN: 10600

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0881 AC: 5989 AN: 68014

Other (OTH) AF: 0.0950 AC: 200 AN: 2106

Alfa AF: 0.0900 Hom.: 3035

Bravo AF: 0.105

Asia WGS AF: 0.0730 AC: 253 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.87
DANN	Benign	0.61
PhyloP100		-0.0020
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: rs12198173; hg19: chr6-32026808;