6-32041812-C-T

Position:

• chr6-32041812-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001365276.2(TNXB):​c.12592G>A​(p.Ala4198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.81

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01037395).
• BP6: Variant 6-32041812-C-T is Benign according to our data. Variant chr6-32041812-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1193708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.12592G>A	p.Ala4198Thr	missense_variant	43/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.12586G>A	p.Ala4196Thr	missense_variant	43/44		NP_061978.6
TNXB	NM_032470.4	c.1879G>A	p.Ala627Thr	missense_variant	12/13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.12592G>A	p.Ala4198Thr	missense_variant	43/44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 86 AN: 123022 Hom.: 0 Cov.: 17 FAILED QC

Gnomad AFR AF: 0.000474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00253

Gnomad SAS AF: 0.00990

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000452

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00233 AC: 307 AN: 131534 Hom.: 0 AF XY: 0.00309 AC XY: 218 AN XY: 70640

Gnomad AFR exome AF: 0.000149

Gnomad AMR exome AF: 0.000258

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00119

Gnomad SAS exome AF: 0.0122

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000716

Gnomad OTH exome AF: 0.000509

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00160 AC: 1325 AN: 825926 Hom.: 0 Cov.: 12 AF XY: 0.00205 AC XY: 869 AN XY: 423872

Gnomad4 AFR exome AF: 0.000301

Gnomad4 AMR exome AF: 0.000350

Gnomad4 ASJ exome AF: 0.0000482

Gnomad4 EAS exome AF: 0.00117

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.000247

Gnomad4 NFE exome AF: 0.000627

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000698 AC: 86 AN: 123146 Hom.: 0 Cov.: 17 AF XY: 0.000863 AC XY: 51 AN XY: 59086

Gnomad4 AFR AF: 0.000472

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00254

Gnomad4 SAS AF: 0.00990

Gnomad4 FIN AF: 0.000120

Gnomad4 NFE AF: 0.000452

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000960 Hom.: 0

ExAC AF: 0.00339 AC: 253

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TNXB: PP2, BS1 -

Ehlers-Danlos syndrome due to tenascin-X deficiency;C4014831:Vesicoureteral reflux 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.030	.;.;.;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;T;T
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	.;.;N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.040	.;.;D;T;.
Sift4G	Uncertain	0.0030	.;.;D;T;D
Vest4		0.57, 0.27
MVP		0.42
MPC		2.9
ClinPred		0.061	T
GERP RS		4.7
Varity_R		0.17
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs756508366; hg19: chr6-32009589;