rs17207895

chr6-32052735-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365276.2(TNXB):c.9050A>G(p.Lys3017Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,740 control chromosomes in the GnomAD database, including 751 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 32)
  • Exomes 𝑓: 0.020 (658 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71

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=0.0028343797).
• BP6: Variant 6-32052735-T-C is Benign according to our data. Variant chr6-32052735-T-C is described in ClinVar as [Benign]. Clinvar id is 261173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32052735-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0198 (3011/152226) while in subpopulation NFE AF= 0.0239 (1626/68008). AF 95% confidence interval is 0.0229. There are 93 homozygotes in gnomad4. There are 1466 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 93 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.9050A>G	p.Lys3017Arg	missense_variant	26/44	ENST00000644971.2
TNXB	NM_019105.8	c.9044A>G	p.Lys3015Arg	missense_variant	26/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.9050A>G	p.Lys3017Arg	missense_variant	26/44		NM_001365276.2
TNXB	ENST00000647633.1	c.9791A>G	p.Lys3264Arg	missense_variant	27/45			P1
TNXB	ENST00000375244.7	c.9050A>G	p.Lys3017Arg	missense_variant	26/44	5

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3012 AN: 152108 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0239 AC: 5899 AN: 246360 Hom.: 216 AF XY: 0.0243 AC XY: 3260 AN XY: 134152

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.00173

Gnomad SAS exome AF: 0.00441

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0200 AC: 29197 AN: 1461514 Hom.: 658 Cov.: 32 AF XY: 0.0205 AC XY: 14886 AN XY: 727048

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.00103

Gnomad4 SAS exome AF: 0.00435

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.0198 AC: 3011 AN: 152226 Hom.: 93 Cov.: 32 AF XY: 0.0197 AC XY: 1466 AN XY: 74418

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0263 Hom.: 71

Bravo AF: 0.0193

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00453 AC: 12

ESP6500EA AF: 0.0239 AC: 123

ExAC AF: 0.0224 AC: 2709

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0345

EpiControl AF: 0.0357

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 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	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
Vest4		0.13
ClinPred		0.018	T
GERP RS		3.2
Varity_R		0.085

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: rs17207895; hg19: chr6-32020512; COSMIC: COSV99056686;