rs2894233

Variant names:

• chr6-32043901-A-G
• rs2894233
• NM_001365276.2:c.11387-9T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-32043901-A-G
• chr6-32043901-A-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.11387-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,610,014 control chromosomes in the GnomAD database, including 408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 27)
  • Exomes 𝑓: 0.020 (379 hom.)
• Consequence: TNXB NM_001365276.2 intron
• Scores: Splicing: ADA: 0.0001661
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.858
• Publications: 5 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=-0.86).
• BP6: Variant 6-32043901-A-G is Benign according to our data. Variant chr6-32043901-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2343/151874) while in subpopulation NFE AF = 0.0251 (1706/67912). AF 95% confidence interval is 0.0241. There are 29 homozygotes in GnomAd4. There are 1071 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11387-9T>C		intron_variant	Intron 34 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.12128-9T>C		intron_variant	Intron 35 of 44		NP_001415264.1
TNXB	NM_019105.8	c.11381-9T>C		intron_variant	Intron 34 of 43		NP_061978.6
TNXB	NM_032470.4	c.674-9T>C		intron_variant	Intron 3 of 12		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11387-9T>C		intron_variant	Intron 34 of 43		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2340 AN: 151756 Hom.: 29 Cov.: 27

Gnomad AFR AF: 0.00710

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00682

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.0139 AC: 3488 AN: 250188 AF XY: 0.0138

Gnomad AFR exome AF: 0.00698

Gnomad AMR exome AF: 0.00623

Gnomad ASJ exome AF: 0.00568

Gnomad EAS exome AF: 0.000926

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0195 AC: 28468 AN: 1458140 Hom.: 379 Cov.: 34 AF XY: 0.0192 AC XY: 13947 AN XY: 725512

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00631 AC: 211 AN: 33432

American (AMR) AF: 0.00643 AC: 287 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 168 AN: 26120

East Asian (EAS) AF: 0.00123 AC: 49 AN: 39682

South Asian (SAS) AF: 0.00260 AC: 224 AN: 86112

European-Finnish (FIN) AF: 0.0175 AC: 929 AN: 52972

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5758

European-Non Finnish (NFE) AF: 0.0231 AC: 25590 AN: 1109110

Other (OTH) AF: 0.0162 AC: 977 AN: 60292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0154 AC: 2343 AN: 151874 Hom.: 29 Cov.: 27 AF XY: 0.0144 AC XY: 1071 AN XY: 74242

African (AFR) AF: 0.00711 AC: 294 AN: 41364

American (AMR) AF: 0.00681 AC: 104 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5150

South Asian (SAS) AF: 0.00271 AC: 13 AN: 4802

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1706 AN: 67912

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.0213 Hom.: 11

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Feb 24, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome Benign:1

Jun 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency;C4014831:Vesicoureteral reflux 8 Benign:1

Mar 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	16
DANN	Benign	0.39
PhyloP100		0.86
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.078
SpliceAI score (max)		0.14		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: rs2894233; hg19: chr6-32011678;