rs199953230

Positions:

• chr6-32041874-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.12530G>A​(p.Ser4177Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.067 (23 hom., cov: 12)
  • Exomes 𝑓: 0.063 (733 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: 0.728

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=0.001997441).
• BP6: Variant 6-32041874-C-T is Benign according to our data. Variant chr6-32041874-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190377.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr6-32041874-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.12530G>A	p.Ser4177Asn	missense_variant	43/44	ENST00000644971.2
TNXB	NM_019105.8	c.12524G>A	p.Ser4175Asn	missense_variant	43/44
TNXB	NM_032470.4	c.1817G>A	p.Ser606Asn	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.12530G>A	p.Ser4177Asn	missense_variant	43/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5778 AN: 86018 Hom.: 23 Cov.: 12 FAILED QC

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0690

Gnomad AMR AF: 0.0635

Gnomad ASJ AF: 0.0770

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.0265

Gnomad NFE AF: 0.0503

Gnomad OTH AF: 0.0685

GnomAD4 exome AF: 0.0630 AC: 32038 AN: 508402 Hom.: 733 Cov.: 6 AF XY: 0.0664 AC XY: 17868 AN XY: 268916

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.0596

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.00974

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.0564

Gnomad4 NFE exome AF: 0.0578

Gnomad4 OTH exome AF: 0.0619

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0672 AC: 5787 AN: 86100 Hom.: 23 Cov.: 12 AF XY: 0.0684 AC XY: 2787 AN XY: 40722

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0633

Gnomad4 ASJ AF: 0.0770

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.0711

Gnomad4 FIN AF: 0.0294

Gnomad4 NFE AF: 0.0503

Gnomad4 OTH AF: 0.0673

Alfa AF: 0.106 Hom.: 64

ExAC AF: 0.0764 AC: 2582

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	Benign	0.050
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.0021	.;.;.;.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.018	.;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	1.8	.;.;N;N;.
REVEL	Benign	0.22
Sift	Benign	0.55	.;.;T;T;.
Sift4G	Benign	1.0	.;.;T;T;T
Vest4		0.060, 0.092
MPC		1.5
ClinPred		0.0059	T
GERP RS		4.7
Varity_R		0.061
gMVP		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199953230; hg19: chr6-32009651; COSMIC: COSV64475162; COSMIC: COSV64475162;