rs2894232

Positions:

• chr6-32043867-A-G
• chr6-32043867-A-T

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.11412T>C​(p.Asp3804Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,612,924 control chromosomes in the GnomAD database, including 13,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1891 hom., cov: 27)
  • Exomes 𝑓: 0.12 (11872 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.91

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]

TNXB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-32043867-A-G is Benign according to our data. Variant chr6-32043867-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32043867-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11412T>C	p.Asp3804Asp	synonymous_variant	35/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.11406T>C	p.Asp3802Asp	synonymous_variant	35/44		NP_061978.6
TNXB	NM_032470.4	c.699T>C	p.Asp233Asp	synonymous_variant	4/13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11412T>C	p.Asp3804Asp	synonymous_variant	35/44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22110 AN: 151630 Hom.: 1883 Cov.: 27

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.0756

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.138 AC: 34759 AN: 251186 Hom.: 2955 AF XY: 0.143 AC XY: 19451 AN XY: 135814

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.0809

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.117 AC: 170645 AN: 1461176 Hom.: 11872 Cov.: 34 AF XY: 0.121 AC XY: 87866 AN XY: 726948

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.181

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.0838

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.146 AC: 22142 AN: 151748 Hom.: 1891 Cov.: 27 AF XY: 0.148 AC XY: 10944 AN XY: 74172

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.0756

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.176

Alfa AF: 0.120 Hom.: 647

Bravo AF: 0.152

Asia WGS AF: 0.257 AC: 896 AN: 3478

EpiCase AF: 0.111

EpiControl AF: 0.111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.016
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2894232; hg19: chr6-32011644; COSMIC: COSV64489968; COSMIC: COSV64489968;