6-32081646-C-T

Variant names:

• chr6-32081646-C-T
• rs12211410
• NM_001365276.2:c.3764G>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.3764G>A​(p.Arg1255His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,590,232 control chromosomes in the GnomAD database, including 6,466 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 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. R1255G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.085 (606 hom., cov: 31)
  • Exomes 𝑓: 0.085 (5860 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.58
• Publications: 33 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)

ENSG00000294466 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013581812).
• BP6: Variant 6-32081646-C-T is Benign according to our data. Variant chr6-32081646-C-T is described in ClinVar as Benign. ClinVar VariationId is 261137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.3764G>A	p.Arg1255His	missense_variant	Exon 10 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.4505G>A	p.Arg1502His	missense_variant	Exon 11 of 45		NP_001415264.1
TNXB	NM_019105.8	c.3764G>A	p.Arg1255His	missense_variant	Exon 10 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.3764G>A	p.Arg1255His	missense_variant	Exon 10 of 44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 12907 AN: 151686 Hom.: 611 Cov.: 31

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0877

Gnomad OTH AF: 0.0801

GnomAD2 exomes AF: 0.0770 AC: 16610 AN: 215686 AF XY: 0.0813

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0337

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0805

Gnomad OTH exome AF: 0.0790

GnomAD4 exome AF: 0.0852 AC: 122495 AN: 1438428 Hom.: 5860 Cov.: 33 AF XY: 0.0861 AC XY: 61338 AN XY: 712660

African (AFR) AF: 0.108 AC: 3579 AN: 33122

American (AMR) AF: 0.0440 AC: 1855 AN: 42164

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2665 AN: 25704

East Asian (EAS) AF: 0.0205 AC: 803 AN: 39114

South Asian (SAS) AF: 0.128 AC: 10543 AN: 82290

European-Finnish (FIN) AF: 0.0522 AC: 2617 AN: 50090

Middle Eastern (MID) AF: 0.0716 AC: 411 AN: 5738

European-Non Finnish (NFE) AF: 0.0860 AC: 94654 AN: 1100770

Other (OTH) AF: 0.0903 AC: 5368 AN: 59436

GnomAD4 genome AF: 0.0850 AC: 12904 AN: 151804 Hom.: 606 Cov.: 31 AF XY: 0.0842 AC XY: 6245 AN XY: 74192

African (AFR) AF: 0.100 AC: 4136 AN: 41364

American (AMR) AF: 0.0434 AC: 662 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3468

East Asian (EAS) AF: 0.0356 AC: 184 AN: 5162

South Asian (SAS) AF: 0.150 AC: 721 AN: 4792

European-Finnish (FIN) AF: 0.0540 AC: 569 AN: 10544

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0877 AC: 5954 AN: 67898

Other (OTH) AF: 0.0792 AC: 167 AN: 2108

Alfa AF: 0.0862 Hom.: 1949

Bravo AF: 0.0855

TwinsUK AF: 0.0787 AC: 292

ALSPAC AF: 0.0786 AC: 303

ESP6500AA AF: 0.0943 AC: 352

ESP6500EA AF: 0.0880 AC: 722

ExAC AF: 0.0696 AC: 8365

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 04, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.0010
DANN	Benign	0.67
DEOGEN2	Benign	0.023	T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.14	.;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.49	.;.;N;.
REVEL	Benign	0.020
Sift	Benign	0.56	.;.;T;.
Sift4G	Benign	1.0	.;.;T;T
Vest4		0.010
ClinPred		0.00030	T
GERP RS		-2.7
Varity_R		0.016
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12211410; hg19: chr6-32049423;