6-32061638-T-C

Position:

• chr6-32061638-T-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.7251A>G​(p.Leu2417Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,612,278 control chromosomes in the GnomAD database, including 248,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23052 hom., cov: 30)
  • Exomes 𝑓: 0.55 (225263 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.472

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=-0.69).
• BP6: Variant 6-32061638-T-C is Benign according to our data. Variant chr6-32061638-T-C is described in ClinVar as [Benign]. Clinvar id is 261156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32061638-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.7251A>G	p.Leu2417Leu	synonymous_variant	21/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.7251A>G	p.Leu2417Leu	synonymous_variant	21/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.7251A>G	p.Leu2417Leu	synonymous_variant	21/44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.7992A>G	p.Leu2664Leu	synonymous_variant	22/45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.7251A>G	p.Leu2417Leu	synonymous_variant	21/44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82731 AN: 151648 Hom.: 23040 Cov.: 30

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.576

GnomAD3 exomes AF: 0.601 AC: 147134 AN: 244634 Hom.: 45453 AF XY: 0.610 AC XY: 81572 AN XY: 133660

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.678

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.601

Gnomad SAS exome AF: 0.753

Gnomad FIN exome AF: 0.557

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.550 AC: 802625 AN: 1460512 Hom.: 225263 Cov.: 98 AF XY: 0.557 AC XY: 404837 AN XY: 726532

Gnomad4 AFR exome AF: 0.483

Gnomad4 AMR exome AF: 0.673

Gnomad4 ASJ exome AF: 0.679

Gnomad4 EAS exome AF: 0.636

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.553

Gnomad4 NFE exome AF: 0.524

Gnomad4 OTH exome AF: 0.559

GnomAD4 genome AF: 0.546 AC: 82790 AN: 151766 Hom.: 23052 Cov.: 30 AF XY: 0.554 AC XY: 41069 AN XY: 74170

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.625

Gnomad4 ASJ AF: 0.683

Gnomad4 EAS AF: 0.618

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.574

Alfa AF: 0.529 Hom.: 8414

Bravo AF: 0.545

EpiCase AF: 0.572

EpiControl AF: 0.579

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

-

- -

Vesicoureteral reflux 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency 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

Sep 20, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 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	-0.69
CADD	Benign	7.4
DANN	Benign	0.82

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: rs204886; hg19: chr6-32029415; COSMIC: COSV64472594; COSMIC: COSV64472594;