6-32043458-C-T

Position:

• chr6-32043458-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.11629G>A​(p.Val3877Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (7338 hom., cov: 8)
  • Exomes 𝑓: 0.51 (68106 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.115

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1128426E-5).
• BP6: Variant 6-32043458-C-T is Benign according to our data. Variant chr6-32043458-C-T is described in ClinVar as [Benign]. Clinvar id is 261114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32043458-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11629G>A	p.Val3877Ile	missense_variant	36/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.11623G>A	p.Val3875Ile	missense_variant	36/44		NP_061978.6
TNXB	NM_032470.4	c.916G>A	p.Val306Ile	missense_variant	5/13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11629G>A	p.Val3877Ile	missense_variant	36/44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 29244 AN: 62378 Hom.: 7336 Cov.: 8

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.501

GnomAD3 exomes AF: 0.516 AC: 45116 AN: 87412 Hom.: 12067 AF XY: 0.515 AC XY: 23374 AN XY: 45364

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.639

Gnomad EAS exome AF: 0.370

Gnomad SAS exome AF: 0.594

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.509

GnomAD4 exome AF: 0.511 AC: 259498 AN: 507536 Hom.: 68106 Cov.: 5 AF XY: 0.518 AC XY: 138501 AN XY: 267406

Gnomad4 AFR exome AF: 0.452

Gnomad4 AMR exome AF: 0.598

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.452

Gnomad4 SAS exome AF: 0.606

Gnomad4 FIN exome AF: 0.488

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.507

GnomAD4 genome AF: 0.469 AC: 29274 AN: 62454 Hom.: 7338 Cov.: 8 AF XY: 0.472 AC XY: 12918 AN XY: 27370

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.544

Gnomad4 ASJ AF: 0.635

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.565

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.500

Alfa AF: 0.504 Hom.: 3489

Bravo AF: 0.501

ExAC AF: 0.335 AC: 20900

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.033	T;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.60	.;T;T;T;T
MetaRNN	Benign	0.000011	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.45	.;.;N;N;.
REVEL	Benign	0.033
Sift	Benign	0.62	.;.;T;T;.
Sift4G	Benign	0.17	.;.;T;T;T
Vest4		0.031, 0.056
MPC		0.28
ClinPred		0.00073	T
GERP RS		0.73
Varity_R		0.028
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2856453; hg19: chr6-32011235; COSMIC: COSV64472768; COSMIC: COSV64472768;