rs2894232

Variant names:

• chr6-32043867-A-G
• rs2894232
• NM_001365276.2:c.11412T>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 261108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.11412T>C	p.Asp3804Asp	synonymous	Exon 35 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.12153T>C	p.Asp4051Asp	synonymous	Exon 36 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.11406T>C	p.Asp3802Asp	synonymous	Exon 35 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.11412T>C	p.Asp3804Asp	synonymous	Exon 35 of 44	ENSP00000496448.1
	TNXB	ENST00000451343.4	TSL:1	c.699T>C	p.Asp233Asp	synonymous	Exon 4 of 13	ENSP00000407685.1
	TNXB	ENST00000490077.5	TSL:1	n.1239T>C		non_coding_transcript_exon	Exon 5 of 14

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

GnomAD2 exomes AF: 0.138 AC: 34759 AN: 251186 AF XY: 0.143

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 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

African (AFR) AF: 0.229 AC: 7669 AN: 33462

American (AMR) AF: 0.120 AC: 5381 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2851 AN: 26136

East Asian (EAS) AF: 0.181 AC: 7183 AN: 39698

South Asian (SAS) AF: 0.254 AC: 21920 AN: 86216

European-Finnish (FIN) AF: 0.0838 AC: 4448 AN: 53062

Middle Eastern (MID) AF: 0.218 AC: 1260 AN: 5768

European-Non Finnish (NFE) AF: 0.101 AC: 112009 AN: 1111722

Other (OTH) AF: 0.131 AC: 7924 AN: 60390

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

African (AFR) AF: 0.219 AC: 9044 AN: 41340

American (AMR) AF: 0.149 AC: 2275 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 383 AN: 3464

East Asian (EAS) AF: 0.158 AC: 815 AN: 5142

South Asian (SAS) AF: 0.221 AC: 1057 AN: 4774

European-Finnish (FIN) AF: 0.0756 AC: 797 AN: 10548

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7325 AN: 67906

Other (OTH) AF: 0.176 AC: 371 AN: 2110

Alfa AF: 0.123 Hom.: 744

Bravo AF: 0.152

Asia WGS AF: 0.257 AC: 896 AN: 3478

EpiCase AF: 0.111

EpiControl AF: 0.111

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.016
DANN	Benign	0.42
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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