rs150379644

Positions:

• chr6-32067653-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365276.2(TNXB):​c.6544+8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,612,232 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (23 hom.)
• Consequence: TNXB NM_001365276.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001493
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.24

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 6-32067653-A-T is Benign according to our data. Variant chr6-32067653-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261149.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.6544+8T>A		splice_region_variant, intron_variant		ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.6544+8T>A		splice_region_variant, intron_variant			NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.6544+8T>A		splice_region_variant, intron_variant			NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.7285+8T>A		splice_region_variant, intron_variant				ENSP00000497649.1
TNXB	ENST00000375244.7	c.6544+8T>A		splice_region_variant, intron_variant		5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00331 AC: 815 AN: 246050 Hom.: 3 AF XY: 0.00364 AC XY: 486 AN XY: 133644

Gnomad AFR exome AF: 0.000584

Gnomad AMR exome AF: 0.00303

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.000335

Gnomad SAS exome AF: 0.00478

Gnomad FIN exome AF: 0.00313

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00450

GnomAD4 exome AF: 0.00387 AC: 5648 AN: 1459932 Hom.: 23 Cov.: 32 AF XY: 0.00401 AC XY: 2910 AN XY: 725998

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.00200

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00497

Gnomad4 FIN exome AF: 0.00261

Gnomad4 NFE exome AF: 0.00418

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74480

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00323 Hom.: 1

Bravo AF: 0.00290

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2023	Variant summary: TNXB c.6544+8T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0033 in 246050 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency does not allow conclusions about variant significance. c.6544+8T>A has been reported in the literature in at least one individual affected with vesicoureteral reflux (e.g., Gbadegesin_2013), without strong evidence for causality (lack of co-segregation and co-occurrence data, etc.). This report therefore does not allow conclusions about association of the variant with Ehlers-Danlos Syndrome, Classic-Like, 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) have cited the variant, with one lab classifying the variant as benign, one lab classifying it as likely benign, and one lab classifying it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

TNXB NM_019105.6 exon 18 c.6544+8T>A: This variant has not been reported in the literature but is present in 0.4% (146/30538) of South Asian alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/6-32035430-A-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:261149). This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 24, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

TNXB: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.46
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs150379644; hg19: chr6-32035430;