6-32056126-G-C

Variant names:

• chr6-32056126-G-C
• rs440160
• NM_001365276.2:c.8192C>G

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.8192C>G​(p.Pro2731Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,612,582 control chromosomes in the GnomAD database, including 2,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. P2731L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.052 (286 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1724 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.79
• Publications: 12 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=0.0020225942).
• BP6: Variant 6-32056126-G-C is Benign according to our data. Variant chr6-32056126-G-C is described in ClinVar as Benign. ClinVar VariationId is 261168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0954 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.8192C>G	p.Pro2731Arg	missense	Exon 24 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.8933C>G	p.Pro2978Arg	missense	Exon 25 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.8192C>G	p.Pro2731Arg	missense	Exon 24 of 44	NP_061978.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.8192C>G	p.Pro2731Arg	missense	Exon 24 of 44	ENSP00000496448.1
	TNXB	ENST00000647633.1		c.8933C>G	p.Pro2978Arg	missense	Exon 25 of 45	ENSP00000497649.1
	TNXB	ENST00000375244.7	TSL:5	c.8192C>G	p.Pro2731Arg	missense	Exon 24 of 44	ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 7921 AN: 152054 Hom.: 287 Cov.: 32

Gnomad AFR AF: 0.0981

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0524

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0547

GnomAD2 exomes AF: 0.0308 AC: 7499 AN: 243560 AF XY: 0.0289

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0210

Gnomad EAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00409

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0403

GnomAD4 exome AF: 0.0434 AC: 63327 AN: 1460410 Hom.: 1724 Cov.: 32 AF XY: 0.0413 AC XY: 29975 AN XY: 726500

African (AFR) AF: 0.0966 AC: 3235 AN: 33480

American (AMR) AF: 0.0395 AC: 1767 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 603 AN: 26134

East Asian (EAS) AF: 0.000831 AC: 33 AN: 39698

South Asian (SAS) AF: 0.000951 AC: 82 AN: 86254

European-Finnish (FIN) AF: 0.00483 AC: 252 AN: 52180

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5768

European-Non Finnish (NFE) AF: 0.0491 AC: 54642 AN: 1111822

Other (OTH) AF: 0.0434 AC: 2620 AN: 60354

GnomAD4 genome AF: 0.0521 AC: 7927 AN: 152172 Hom.: 286 Cov.: 32 AF XY: 0.0489 AC XY: 3638 AN XY: 74386

African (AFR) AF: 0.0980 AC: 4065 AN: 41500

American (AMR) AF: 0.0524 AC: 801 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10608

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0409 AC: 2784 AN: 67988

Other (OTH) AF: 0.0541 AC: 114 AN: 2106

Alfa AF: 0.0201 Hom.: 9

Bravo AF: 0.0596

TwinsUK AF: 0.0531 AC: 197

ALSPAC AF: 0.0586 AC: 226

ESP6500AA AF: 0.0843 AC: 201

ESP6500EA AF: 0.0418 AC: 209

ExAC AF: 0.0291 AC: 3441

EpiCase AF: 0.0393

EpiControl AF: 0.0411

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Dec 21, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.72	T
PhyloP100		1.8
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.24
Sift	Benign	0.041	D
Sift4G	Pathogenic	0.0	D
Vest4		0.14
ClinPred		0.029	T
GERP RS		4.5
Varity_R		0.18
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs440160; hg19: chr6-32023903;