rs59619270

Positions:

• chr6-32061512-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365276.2(TNXB):​c.7377C>T​(p.Gly2459=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,613,460 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (142 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -7.53

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=-0.89).
• BP6: Variant 6-32061512-G-A is Benign according to our data. Variant chr6-32061512-G-A is described in ClinVar as [Benign]. Clinvar id is 261158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32061512-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-7.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.7377C>T	p.Gly2459=	synonymous_variant	21/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.7377C>T	p.Gly2459=	synonymous_variant	21/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.7377C>T	p.Gly2459=	synonymous_variant	21/44		NM_001365276.2	ENSP00000496448
TNXB	ENST00000647633.1	c.8118C>T	p.Gly2706=	synonymous_variant	22/45			ENSP00000497649	P1
TNXB	ENST00000375244.7	c.7377C>T	p.Gly2459=	synonymous_variant	21/44	5		ENSP00000364393

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3512 AN: 151928 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00606 AC: 1504 AN: 248104 Hom.: 74 AF XY: 0.00465 AC XY: 627 AN XY: 134822

Gnomad AFR exome AF: 0.0821

Gnomad AMR exome AF: 0.00496

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000383

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00249 AC: 3639 AN: 1461414 Hom.: 142 Cov.: 121 AF XY: 0.00217 AC XY: 1578 AN XY: 727006

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.00546

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.00668

GnomAD4 genome AF: 0.0231 AC: 3514 AN: 152046 Hom.: 141 Cov.: 32 AF XY: 0.0224 AC XY: 1665 AN XY: 74342

Gnomad4 AFR AF: 0.0795

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.00728 Hom.: 17

Bravo AF: 0.0271

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

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

Mar 15, 2022

- -

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

Apr 23, 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	-0.89
CADD	Benign	0.20
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs59619270; hg19: chr6-32029289;