chr6-32043901-A-G

Position:

• chr6-32043901-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 261107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32043901-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.11387-9T>C		intron_variant		ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.11381-9T>C		intron_variant			NP_061978.6
TNXB	NM_032470.4	c.674-9T>C		intron_variant			NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.11387-9T>C		intron_variant			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

GnomAD3 exomes AF: 0.0139 AC: 3488 AN: 250188 Hom.: 37 AF XY: 0.0138 AC XY: 1870 AN XY: 135330

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 SAS exome AF: 0.00227

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

Gnomad4 AFR exome AF: 0.00631

Gnomad4 AMR exome AF: 0.00643

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0175

Gnomad4 NFE exome AF: 0.0231

Gnomad4 OTH exome AF: 0.0162

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

Gnomad4 AFR AF: 0.00711

Gnomad4 AMR AF: 0.00681

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.00271

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.0251

Gnomad4 OTH AF: 0.00901

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2016

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 17, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	16
DANN	Benign	0.39
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs2894233; hg19: chr6-32011678;