6-32043458-C-T

Variant names:

• chr6-32043458-C-T
• rs2856453
• NM_001365276.2:c.11629G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3877L) has been classified as Uncertain significance.

• 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
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.11629G>A	p.Val3877Ile	missense	Exon 36 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.12370G>A	p.Val4124Ile	missense	Exon 37 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.11623G>A	p.Val3875Ile	missense	Exon 36 of 44	NP_061978.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.11629G>A	p.Val3877Ile	missense	Exon 36 of 44	ENSP00000496448.1
	TNXB	ENST00000451343.4	TSL:1	c.916G>A	p.Val306Ile	missense	Exon 5 of 13	ENSP00000407685.1
	TNXB	ENST00000490077.5	TSL:1	n.1456G>A		non_coding_transcript_exon	Exon 6 of 14

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

GnomAD2 exomes AF: 0.516 AC: 45116 AN: 87412 AF XY: 0.515

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 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

African (AFR) AF: 0.452 AC: 6667 AN: 14766

American (AMR) AF: 0.598 AC: 18175 AN: 30368

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 10277 AN: 15866

East Asian (EAS) AF: 0.452 AC: 14138 AN: 31260

South Asian (SAS) AF: 0.606 AC: 31696 AN: 52312

European-Finnish (FIN) AF: 0.488 AC: 14786 AN: 30298

Middle Eastern (MID) AF: 0.611 AC: 1320 AN: 2162

European-Non Finnish (NFE) AF: 0.490 AC: 148084 AN: 302208

Other (OTH) AF: 0.507 AC: 14355 AN: 28296

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

African (AFR) AF: 0.418 AC: 5982 AN: 14298

American (AMR) AF: 0.544 AC: 3226 AN: 5928

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 1075 AN: 1694

East Asian (EAS) AF: 0.381 AC: 960 AN: 2518

South Asian (SAS) AF: 0.565 AC: 979 AN: 1732

European-Finnish (FIN) AF: 0.477 AC: 1866 AN: 3916

Middle Eastern (MID) AF: 0.573 AC: 125 AN: 218

European-Non Finnish (NFE) AF: 0.466 AC: 14436 AN: 30986

Other (OTH) AF: 0.500 AC: 387 AN: 774

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

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.12
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.033
Sift	Benign	0.62	T
Sift4G	Benign	0.17	T
Vest4		0.031
MPC		0.28
ClinPred		0.00073	T
GERP RS		0.73
Varity_R		0.028
gMVP		0.11
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2856453; hg19: chr6-32011235; COSMIC: COSV64472768; COSMIC: COSV64472768;