chr6-32049328-A-G

Position:

• chr6-32049328-A-G

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.9699T>C​(p.His3233=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0605 in 1,612,390 control chromosomes in the GnomAD database, including 3,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (286 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3114 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.996

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 (BayesDel_noAF=-0.55).
• BP6: Variant 6-32049328-A-G is Benign according to our data. Variant chr6-32049328-A-G is described in ClinVar as [Benign]. Clinvar id is 261182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32049328-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.9699T>C	p.His3233=	synonymous_variant	28/44	ENST00000644971.2
TNXB	NM_019105.8	c.9693T>C	p.His3231=	synonymous_variant	28/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.9699T>C	p.His3233=	synonymous_variant	28/44		NM_001365276.2
TNXB	ENST00000647633.1	c.10440T>C	p.His3480=	synonymous_variant	29/45			P1
TNXB	ENST00000375244.7	c.9699T>C	p.His3233=	synonymous_variant	28/44	5

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7419 AN: 152058 Hom.: 284 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0991

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0658

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0581 AC: 14337 AN: 246932 Hom.: 565 AF XY: 0.0588 AC XY: 7895 AN XY: 134310

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.0581

Gnomad NFE exome AF: 0.0670

Gnomad OTH exome AF: 0.0550

GnomAD4 exome AF: 0.0618 AC: 90172 AN: 1460214 Hom.: 3114 Cov.: 33 AF XY: 0.0613 AC XY: 44524 AN XY: 726446

Gnomad4 AFR exome AF: 0.00951

Gnomad4 AMR exome AF: 0.0342

Gnomad4 ASJ exome AF: 0.0172

Gnomad4 EAS exome AF: 0.0777

Gnomad4 SAS exome AF: 0.0571

Gnomad4 FIN exome AF: 0.0624

Gnomad4 NFE exome AF: 0.0651

Gnomad4 OTH exome AF: 0.0672

GnomAD4 genome AF: 0.0488 AC: 7432 AN: 152176 Hom.: 286 Cov.: 33 AF XY: 0.0490 AC XY: 3644 AN XY: 74420

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0345

Gnomad4 ASJ AF: 0.0162

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.0746

Gnomad4 FIN AF: 0.0603

Gnomad4 NFE AF: 0.0658

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0548 Hom.: 135

Bravo AF: 0.0439

Asia WGS AF: 0.144 AC: 499 AN: 3478

EpiCase AF: 0.0532

EpiControl AF: 0.0582

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.9
DANN	Benign	0.29

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: rs61740337; hg19: chr6-32017105; COSMIC: COSV64478481; COSMIC: COSV64478481;