rs41270458

Positions:

• chr6-32096119-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365276.2(TNXB):​c.1734C>T​(p.Asp578=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,604,102 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (36 hom., cov: 34)
  • Exomes 𝑓: 0.022 (408 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.78

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-32096119-G-A is Benign according to our data. Variant chr6-32096119-G-A is described in ClinVar as [Benign]. Clinvar id is 261126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32096119-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0183 (2782/151800) while in subpopulation NFE AF= 0.0255 (1730/67866). AF 95% confidence interval is 0.0245. There are 36 homozygotes in gnomad4. There are 1374 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.1734C>T	p.Asp578=	synonymous_variant	3/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.1734C>T	p.Asp578=	synonymous_variant	3/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.1734C>T	p.Asp578=	synonymous_variant	3/44		NM_001365276.2	ENSP00000496448

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2783 AN: 151680 Hom.: 36 Cov.: 34

Gnomad AFR AF: 0.00366

Gnomad AMI AF: 0.00444

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00390

Gnomad SAS AF: 0.0214

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0264

GnomAD3 exomes AF: 0.0222 AC: 4974 AN: 224438 Hom.: 83 AF XY: 0.0236 AC XY: 2894 AN XY: 122568

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.00856

Gnomad EAS exome AF: 0.00463

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0221 AC: 32079 AN: 1452302 Hom.: 408 Cov.: 33 AF XY: 0.0225 AC XY: 16242 AN XY: 721586

Gnomad4 AFR exome AF: 0.00292

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.00798

Gnomad4 EAS exome AF: 0.00494

Gnomad4 SAS exome AF: 0.0253

Gnomad4 FIN exome AF: 0.0347

Gnomad4 NFE exome AF: 0.0232

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0183 AC: 2782 AN: 151800 Hom.: 36 Cov.: 34 AF XY: 0.0185 AC XY: 1374 AN XY: 74192

Gnomad4 AFR AF: 0.00364

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00392

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.0334

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0219 Hom.: 37

Bravo AF: 0.0163

Asia WGS AF: 0.00808 AC: 28 AN: 3478

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

Jun 23, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2019

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	-0.85
CADD	Benign	0.80
DANN	Benign	0.80

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: rs41270458; hg19: chr6-32063896;