rs200523717

chr6-32041884-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001365276.2(TNXB):c.12520G>A(p.Asp4174Asn) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.093 (27 hom., cov: 11)
  • Exomes 𝑓: 0.094 (730 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.03

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008031756).
• BP6: Variant 6-32041884-C-T is Benign according to our data. Variant chr6-32041884-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190376.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr6-32041884-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.12520G>A	p.Asp4174Asn	missense_variant	43/44	ENST00000644971.2
TNXB	NM_019105.8	c.12514G>A	p.Asp4172Asn	missense_variant	43/44
TNXB	NM_032470.4	c.1807G>A	p.Asp603Asn	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.12520G>A	p.Asp4174Asn	missense_variant	43/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7579 AN: 81200 Hom.: 27 Cov.: 11 FAILED QC

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0543

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0987

Gnomad EAS AF: 0.0562

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0481

Gnomad MID AF: 0.0374

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.0930

GnomAD4 exome AF: 0.0936 AC: 46105 AN: 492734 Hom.: 730 Cov.: 6 AF XY: 0.0996 AC XY: 25901 AN XY: 259990

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0685

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.0517

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.0767

Gnomad4 NFE exome AF: 0.0816

Gnomad4 OTH exome AF: 0.0909

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0934 AC: 7588 AN: 81276 Hom.: 27 Cov.: 11 AF XY: 0.0970 AC XY: 3698 AN XY: 38130

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0817

Gnomad4 ASJ AF: 0.0987

Gnomad4 EAS AF: 0.0567

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.0481

Gnomad4 NFE AF: 0.0740

Gnomad4 OTH AF: 0.0915

Alfa AF: 0.123 Hom.: 76

ExAC AF: 0.126 AC: 3546

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Pediatric Services, National Institutes of Health, Clinical Center

Jan 01, 2015

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jun 25, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.0080	T;T;T;T;T
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
Vest4		0.20, 0.58
MPC		2.9
ClinPred		0.017	T
GERP RS		4.7
Varity_R		0.73
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200523717; hg19: chr6-32009661; COSMIC: COSV64475182; COSMIC: COSV64475182;