rs10947230

Variant names:

• chr6-32056618-C-T
• rs10947230
• NM_001365276.2:c.8111G>A

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.8111G>A​(p.Arg2704His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,612,948 control chromosomes in the GnomAD database, including 4,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2704C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.098 (930 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3683 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.27
• Publications: 9 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 (MetaRNN=0.001785636).
• BP6: Variant 6-32056618-C-T is Benign according to our data. Variant chr6-32056618-C-T is described in ClinVar as Benign. ClinVar VariationId is 261166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.8111G>A	p.Arg2704His	missense_variant	Exon 23 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.8852G>A	p.Arg2951His	missense_variant	Exon 24 of 45		NP_001415264.1
TNXB	NM_019105.8	c.8111G>A	p.Arg2704His	missense_variant	Exon 23 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.8111G>A	p.Arg2704His	missense_variant	Exon 23 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.8852G>A	p.Arg2951His	missense_variant	Exon 24 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.8111G>A	p.Arg2704His	missense_variant	Exon 23 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.0980 AC: 14913 AN: 152162 Hom.: 928 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0724

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0856

GnomAD2 exomes AF: 0.0778 AC: 19093 AN: 245378 AF XY: 0.0726

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0923

Gnomad ASJ exome AF: 0.00964

Gnomad EAS exome AF: 0.0888

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.0622

Gnomad OTH exome AF: 0.0649

GnomAD4 exome AF: 0.0642 AC: 93775 AN: 1460668 Hom.: 3683 Cov.: 33 AF XY: 0.0626 AC XY: 45515 AN XY: 726606

African (AFR) AF: 0.163 AC: 5468 AN: 33478

American (AMR) AF: 0.0851 AC: 3807 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26136

East Asian (EAS) AF: 0.0718 AC: 2850 AN: 39694

South Asian (SAS) AF: 0.0336 AC: 2898 AN: 86252

European-Finnish (FIN) AF: 0.159 AC: 8324 AN: 52440

Middle Eastern (MID) AF: 0.0427 AC: 246 AN: 5766

European-Non Finnish (NFE) AF: 0.0597 AC: 66338 AN: 1111832

Other (OTH) AF: 0.0590 AC: 3563 AN: 60354

GnomAD4 genome AF: 0.0980 AC: 14920 AN: 152280 Hom.: 930 Cov.: 32 AF XY: 0.100 AC XY: 7454 AN XY: 74448

African (AFR) AF: 0.162 AC: 6722 AN: 41538

American (AMR) AF: 0.0721 AC: 1104 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.0829 AC: 429 AN: 5178

South Asian (SAS) AF: 0.0395 AC: 191 AN: 4832

European-Finnish (FIN) AF: 0.175 AC: 1859 AN: 10618

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0632 AC: 4298 AN: 68018

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0703 Hom.: 1240

Bravo AF: 0.0948

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.158 AC: 393

ESP6500EA AF: 0.0620 AC: 314

ExAC AF: 0.0767 AC: 9227

Asia WGS AF: 0.0470 AC: 164 AN: 3478

EpiCase AF: 0.0643

EpiControl AF: 0.0615

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Sep 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 24, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;.;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	.;D;D;D
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		2.3
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.2	.;.;D;.
REVEL	Benign	0.16
Sift	Uncertain	0.0060	.;.;D;.
Sift4G	Pathogenic	0.0	.;.;D;D
Vest4		0.18
ClinPred		0.023	T
GERP RS		4.6
Varity_R		0.21
Mutation Taster		=97/3	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: rs10947230; hg19: chr6-32024395; COSMIC: COSV64491307;