rs1150757

Positions:

• chr6-32061428-G-A
• chr6-32061428-G-C

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.7461C>T​(p.Arg2487=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,612,690 control chromosomes in the GnomAD database, including 9,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (479 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9485 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.89

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=-0.78).
• BP6: Variant 6-32061428-G-A is Benign according to our data. Variant chr6-32061428-G-A is described in ClinVar as [Benign]. Clinvar id is 261160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32061428-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.7461C>T	p.Arg2487=	synonymous_variant	21/44	ENST00000644971.2
TNXB	NM_019105.8	c.7461C>T	p.Arg2487=	synonymous_variant	21/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.7461C>T	p.Arg2487=	synonymous_variant	21/44		NM_001365276.2
TNXB	ENST00000647633.1	c.8202C>T	p.Arg2734=	synonymous_variant	22/45			P1
TNXB	ENST00000375244.7	c.7461C>T	p.Arg2487=	synonymous_variant	21/44	5

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9464 AN: 151754 Hom.: 479 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0799

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0468

GnomAD3 exomes AF: 0.0587 AC: 14408 AN: 245576 Hom.: 775 AF XY: 0.0578 AC XY: 7727 AN XY: 133750

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0783

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.0596

GnomAD4 exome AF: 0.101 AC: 147413 AN: 1460818 Hom.: 9485 Cov.: 37 AF XY: 0.0976 AC XY: 70901 AN XY: 726626

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0399

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0807

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.0864

GnomAD4 genome AF: 0.0623 AC: 9461 AN: 151872 Hom.: 479 Cov.: 32 AF XY: 0.0579 AC XY: 4302 AN XY: 74246

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0296

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0799

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.0464

Alfa AF: 0.0734 Hom.: 265

Bravo AF: 0.0570

EpiCase AF: 0.0947

EpiControl AF: 0.0863

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

-

- -

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 24, 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	-0.78
CADD	Benign	0.65
DANN	Benign	0.84

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: rs1150757; hg19: chr6-32029205;