rs116701346

chr6-32046413-G-Achr6-32046413-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001365276.2(TNXB):c.10368C>T(p.Thr3456=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,579,948 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (5 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.07

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-32046413-G-A is Benign according to our data. Variant chr6-32046413-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.07 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.10368C>T	p.Thr3456=	synonymous_variant	31/44	ENST00000644971.2
TNXB	NM_019105.8	c.10362C>T	p.Thr3454=	synonymous_variant	31/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.10368C>T	p.Thr3456=	synonymous_variant	31/44		NM_001365276.2
TNXB	ENST00000490077.5	n.195C>T		non_coding_transcript_exon_variant	1/14	1
TNXB	ENST00000647633.1	c.11109C>T	p.Thr3703=	synonymous_variant	32/45			P1
TNXB	ENST00000375244.7	c.10368C>T	p.Thr3456=	synonymous_variant	31/44	5

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152220 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000808 AC: 195 AN: 241284 Hom.: 0 AF XY: 0.000636 AC XY: 84 AN XY: 132174

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000527

Gnomad ASJ exome AF: 0.000921

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00150

Gnomad NFE exome AF: 0.000408

Gnomad OTH exome AF: 0.000676

GnomAD4 exome AF: 0.000530 AC: 757 AN: 1427610 Hom.: 5 Cov.: 31 AF XY: 0.000517 AC XY: 364 AN XY: 703546

Gnomad4 AFR exome AF: 0.00915

Gnomad4 AMR exome AF: 0.000543

Gnomad4 ASJ exome AF: 0.00116

Gnomad4 EAS exome AF: 0.000180

Gnomad4 SAS exome AF: 0.0000834

Gnomad4 FIN exome AF: 0.00209

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.000967

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74496

Gnomad4 AFR AF: 0.00748

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TNXB: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 24, 2020

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2020

This alteration is classified as likely 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	-0.77
Cadd	Benign	0.18
Dann	Benign	0.65

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: rs116701346; hg19: chr6-32014190;