rs773540524

Variant names:

• chr6-32045345-G-T
• rs773540524
• ENST00000451343.4:c.-126C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The ENST00000451343.4(TNXB):​c.-126C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (0 hom., cov: 19)
  • Exomes 𝑓: 0.013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB ENST00000451343.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.228
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-32045345-G-T is Benign according to our data. Variant chr6-32045345-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 261096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.10607-19C>A		intron_variant	Intron 31 of 43	ENST00000644971.2	NP_001352205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.10607-19C>A		intron_variant	Intron 31 of 43		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1403 AN: 145140 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0229

Gnomad AMR AF: 0.00750

Gnomad ASJ AF: 0.00381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00174

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.00722

GnomAD2 exomes AF: 0.00993 AC: 828 AN: 83362 AF XY: 0.00979

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00739

Gnomad ASJ exome AF: 0.00396

Gnomad EAS exome AF: 0.000228

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0101

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0128 AC: 14808 AN: 1160006 Hom.: 0 Cov.: 18 AF XY: 0.0126 AC XY: 7199 AN XY: 572950

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

African (AFR) AF: 0.00198 AC: 55 AN: 27838

American (AMR) AF: 0.00590 AC: 185 AN: 31344

Ashkenazi Jewish (ASJ) AF: 0.00537 AC: 119 AN: 22168

East Asian (EAS) AF: 0.000257 AC: 9 AN: 34990

South Asian (SAS) AF: 0.00264 AC: 190 AN: 72102

European-Finnish (FIN) AF: 0.0178 AC: 795 AN: 44570

Middle Eastern (MID) AF: 0.00817 AC: 30 AN: 3672

European-Non Finnish (NFE) AF: 0.0147 AC: 12884 AN: 873498

Other (OTH) AF: 0.0109 AC: 541 AN: 49824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00966 AC: 1403 AN: 145258 Hom.: 0 Cov.: 19 AF XY: 0.00951 AC XY: 672 AN XY: 70654

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

African (AFR) AF: 0.00211 AC: 84 AN: 39808

American (AMR) AF: 0.00749 AC: 110 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.00381 AC: 13 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4836

South Asian (SAS) AF: 0.00175 AC: 8 AN: 4582

European-Finnish (FIN) AF: 0.0179 AC: 177 AN: 9904

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0150 AC: 975 AN: 64914

Other (OTH) AF: 0.00714 AC: 14 AN: 1962

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0143 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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	-0.81
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism

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: rs773540524; hg19: chr6-32013122;