rs2395083

Variant names:

• chr6-32043703-G-A
• rs2395083
• NM_001365276.2:c.11530+46C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365276.2(TNXB):​c.11530+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,613,126 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 27)
  • Exomes 𝑓: 0.0036 (11 hom.)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.74
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-32043703-G-A is Benign according to our data. Variant chr6-32043703-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 261110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00362 (5283/1461056) while in subpopulation SAS AF = 0.0118 (1021/86228). AF 95% confidence interval is 0.0112. There are 11 homozygotes in GnomAdExome4. There are 2733 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.11530+46C>T		intron	N/A	NP_001352205.1
	TNXB	NM_001428335.1		c.12271+46C>T		intron	N/A	NP_001415264.1
	TNXB	NM_019105.8		c.11524+46C>T		intron	N/A	NP_061978.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.11530+46C>T		intron	N/A	ENSP00000496448.1
	TNXB	ENST00000451343.4	TSL:1	c.817+46C>T		intron	N/A	ENSP00000407685.1
	TNXB	ENST00000490077.5	TSL:1	n.1357+46C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 463 AN: 151952 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00851

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00325 AC: 813 AN: 250172 AF XY: 0.00366

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.000465

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00362 AC: 5283 AN: 1461056 Hom.: 11 Cov.: 32 AF XY: 0.00376 AC XY: 2733 AN XY: 726854

African (AFR) AF: 0.00173 AC: 58 AN: 33480

American (AMR) AF: 0.00168 AC: 75 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26134

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0118 AC: 1021 AN: 86228

European-Finnish (FIN) AF: 0.000683 AC: 36 AN: 52708

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00347 AC: 3857 AN: 1111932

Other (OTH) AF: 0.00336 AC: 203 AN: 60384

GnomAD4 genome AF: 0.00304 AC: 462 AN: 152070 Hom.: 1 Cov.: 27 AF XY: 0.00280 AC XY: 208 AN XY: 74356

African (AFR) AF: 0.00138 AC: 57 AN: 41446

American (AMR) AF: 0.00216 AC: 33 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.00831 AC: 40 AN: 4812

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00363 AC: 247 AN: 67986

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00323 Hom.: 1

Bravo AF: 0.00323

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Sep 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.60
DANN	Benign	0.83
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2395083; hg19: chr6-32011480;