rs17421133

chr6-32042495-T-A

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.12170A>T(p.Asn4057Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,610,306 control chromosomes in the GnomAD database, including 78,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6422 hom., cov: 23)
  • Exomes 𝑓: 0.31 (72328 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00500

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=0.004891485).
• BP6: Variant 6-32042495-T-A is Benign according to our data. Variant chr6-32042495-T-A is described in ClinVar as [Benign]. Clinvar id is 261120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32042495-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.12170A>T	p.Asn4057Ile	missense_variant	40/44	ENST00000644971.2
TNXB	NM_019105.8	c.12164A>T	p.Asn4055Ile	missense_variant	40/44
TNXB	NM_032470.4	c.1457A>T	p.Asn486Ile	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.12170A>T	p.Asn4057Ile	missense_variant	40/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38708 AN: 151314 Hom.: 6412 Cov.: 23

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.253

GnomAD3 exomes AF: 0.320 AC: 79846 AN: 249888 Hom.: 14563 AF XY: 0.319 AC XY: 43100 AN XY: 135308

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.245

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.305 AC: 445066 AN: 1458874 Hom.: 72328 Cov.: 73 AF XY: 0.306 AC XY: 221805 AN XY: 725826

Gnomad4 AFR exome AF: 0.0506

Gnomad4 AMR exome AF: 0.443

Gnomad4 ASJ exome AF: 0.451

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.289

GnomAD4 genome AF: 0.256 AC: 38724 AN: 151432 Hom.: 6422 Cov.: 23 AF XY: 0.261 AC XY: 19311 AN XY: 74006

Gnomad4 AFR AF: 0.0592

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.254

Alfa AF: 0.318 Hom.: 2585

Bravo AF: 0.249

ESP6500AA AF: 0.0754 AC: 228

ESP6500EA AF: 0.315 AC: 1707

ExAC AF: 0.308 AC: 37441

Asia WGS AF: 0.226 AC: 787 AN: 3474

EpiCase AF: 0.342

EpiControl AF: 0.353

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Vesicoureteral reflux 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 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	0.21
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.19	N
MetaRNN	Benign	0.0049	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.36	T
Vest4		0.41, 0.33
MPC		0.42
ClinPred		0.025	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.42

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: rs17421133; hg19: chr6-32010272; COSMIC: COSV64492111; COSMIC: COSV64492111;