6-32061406-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.7483G>A(p.Gly2495Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,612,046 control chromosomes in the GnomAD database, including 14,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1844 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12568 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.02

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006383598).
• BP6: Variant 6-32061406-C-T is Benign according to our data. Variant chr6-32061406-C-T is described in ClinVar as [Benign]. Clinvar id is 261161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32061406-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.7483G>A	p.Gly2495Ser	missense_variant	21/44	ENST00000644971.2
TNXB	NM_019105.8	c.7483G>A	p.Gly2495Ser	missense_variant	21/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.7483G>A	p.Gly2495Ser	missense_variant	21/44		NM_001365276.2
TNXB	ENST00000647633.1	c.8224G>A	p.Gly2742Ser	missense_variant	22/45			P1
TNXB	ENST00000375244.7	c.7483G>A	p.Gly2495Ser	missense_variant	21/44	5

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20203 AN: 151562 Hom.: 1839 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.0949

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.135 AC: 33104 AN: 245182 Hom.: 3436 AF XY: 0.148 AC XY: 19700 AN XY: 133522

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0884

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.351

Gnomad FIN exome AF: 0.0658

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.109 AC: 159380 AN: 1460366 Hom.: 12568 Cov.: 32 AF XY: 0.117 AC XY: 84958 AN XY: 726370

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0949

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.0682

Gnomad4 NFE exome AF: 0.0891

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.133 AC: 20227 AN: 151680 Hom.: 1844 Cov.: 32 AF XY: 0.137 AC XY: 10158 AN XY: 74132

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.0623

Gnomad4 NFE AF: 0.0949

Gnomad4 OTH AF: 0.166

Alfa AF: 0.107 Hom.: 2213

Bravo AF: 0.138

TwinsUK AF: 0.0836 AC: 310

ALSPAC AF: 0.0947 AC: 365

ESP6500AA AF: 0.171 AC: 479

ESP6500EA AF: 0.0869 AC: 452

ExAC AF: 0.141 AC: 17066

Asia WGS AF: 0.241 AC: 840 AN: 3476

EpiCase AF: 0.102

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 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 -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

This variant is associated with the following publications: (PMID: 16574953) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2018

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	0.19
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.071	T;.;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.073	N
MetaRNN	Benign	0.0064	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.42	T
Vest4		0.11
ClinPred		0.071	T
GERP RS		4.4
Varity_R		0.097

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

Publications

LitVar

Other links and lift over

dbSNP: rs2269429; hg19: chr6-32029183; COSMIC: COSV64483692; COSMIC: COSV64483692;