6-32042349-C-T

Position:

• chr6-32042349-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001365276.2(TNXB):​c.12224G>A​(p.Arg4075His) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0068 (1 hom., cov: 19)
  • Exomes 𝑓: 0.045 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.08

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005153835).
• BP6: Variant 6-32042349-C-T is Benign according to our data. Variant chr6-32042349-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.12224G>A	p.Arg4075His	missense_variant	41/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.12218G>A	p.Arg4073His	missense_variant	41/44		NP_061978.6
TNXB	NM_032470.4	c.1511G>A	p.Arg504His	missense_variant	10/13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.12224G>A	p.Arg4075His	missense_variant	41/44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 848 AN: 124242 Hom.: 1 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00120

Gnomad AMR AF: 0.00474

Gnomad ASJ AF: 0.00129

Gnomad EAS AF: 0.00705

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.00403

Gnomad MID AF: 0.0149

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00646

GnomAD3 exomes AF: 0.0317 AC: 6690 AN: 210924 Hom.: 1 AF XY: 0.0355 AC XY: 4052 AN XY: 114162

Gnomad AFR exome AF: 0.0688

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0269

Gnomad SAS exome AF: 0.0827

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0266

Gnomad OTH exome AF: 0.0256

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0445 AC: 55050 AN: 1236720 Hom.: 6 Cov.: 27 AF XY: 0.0430 AC XY: 26655 AN XY: 619428

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.0194

Gnomad4 SAS exome AF: 0.0609

Gnomad4 FIN exome AF: 0.00695

Gnomad4 NFE exome AF: 0.0463

Gnomad4 OTH exome AF: 0.0430

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00684 AC: 850 AN: 124342 Hom.: 1 Cov.: 19 AF XY: 0.00681 AC XY: 413 AN XY: 60682

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.00474

Gnomad4 ASJ AF: 0.00129

Gnomad4 EAS AF: 0.00730

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.00403

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00637

Alfa AF: 0.0163 Hom.: 0

ExAC AF: 0.0869 AC: 10532

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	research	Pediatric Services, National Institutes of Health, Clinical Center	Jan 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;.;.;.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	.;T;T;D;D
MetaRNN	Benign	0.0052	T;T;T;T;T
MetaSVM	Pathogenic	0.89	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	.;.;D;D;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;.;D;D;.
Sift4G	Pathogenic	0.0010	.;.;D;D;D
Vest4		0.21, 0.72
MPC		3.4
ClinPred		0.072	T
GERP RS		4.8
Varity_R		0.67
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201510617; hg19: chr6-32010126; COSMIC: COSV64472555; COSMIC: COSV64472555;