rs61740712

chr6-32053578-G-Achr6-32053578-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001365276.2(TNXB):c.8601C>T(p.Pro2867=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00982 in 1,613,638 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (79 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.39

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 6-32053578-G-A is Benign according to our data. Variant chr6-32053578-G-A is described in ClinVar as [Benign]. Clinvar id is 261170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32053578-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.39 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.8601C>T	p.Pro2867=	synonymous_variant	25/44	ENST00000644971.2
TNXB	NM_019105.8	c.8595C>T	p.Pro2865=	synonymous_variant	25/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.8601C>T	p.Pro2867=	synonymous_variant	25/44		NM_001365276.2
TNXB	ENST00000647633.1	c.9342C>T	p.Pro3114=	synonymous_variant	26/45			P1
TNXB	ENST00000375244.7	c.8601C>T	p.Pro2867=	synonymous_variant	25/44	5

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1311 AN: 152144 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.00961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00859 AC: 2121 AN: 246948 Hom.: 13 AF XY: 0.00902 AC XY: 1213 AN XY: 134438

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00568

Gnomad ASJ exome AF: 0.00590

Gnomad EAS exome AF: 0.000948

Gnomad SAS exome AF: 0.00788

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.00995 AC: 14535 AN: 1461376 Hom.: 79 Cov.: 33 AF XY: 0.0101 AC XY: 7335 AN XY: 726982

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.00673

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.00812

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00827

GnomAD4 genome AF: 0.00860 AC: 1309 AN: 152262 Hom.: 5 Cov.: 32 AF XY: 0.00884 AC XY: 658 AN XY: 74438

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.00961

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.0105 Hom.: 5

Bravo AF: 0.00811

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00895

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TNXB: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2019	- -

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 02, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 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	-0.45
Cadd	Benign	0.47
Dann	Benign	0.52

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: rs61740712; hg19: chr6-32021355;