6-32041679-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001365276.2(TNXB):c.12633+92T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,112,634 control chromosomes in the GnomAD database, including 32,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (6009 hom., cov: 23)
  • Exomes 𝑓: 0.15 (26531 hom.)
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.390

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]

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-32041679-A-G is Benign according to our data. Variant chr6-32041679-A-G is described in ClinVar as [Benign]. Clinvar id is 1284242.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32041679-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.12633+92T>C		intron_variant		ENST00000644971.2
CYP21A2	NM_000500.9			downstream_gene_variant		ENST00000644719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.12633+92T>C		intron_variant			NM_001365276.2
CYP21A2	ENST00000644719.2			downstream_gene_variant			NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 35469 AN: 142214 Hom.: 6000 Cov.: 23

Gnomad AFR AF: 0.0686

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.319

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.146 AC: 142125 AN: 970316 Hom.: 26531 Cov.: 18 AF XY: 0.153 AC XY: 75147 AN XY: 490408

Gnomad4 AFR exome AF: 0.0294

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.225

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.249 AC: 35492 AN: 142318 Hom.: 6009 Cov.: 23 AF XY: 0.253 AC XY: 17501 AN XY: 69146

Gnomad4 AFR AF: 0.0686

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.241

Alfa AF: 0.293 Hom.: 847

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.11
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3128757; hg19: chr6-32009456; COSMIC: COSV64474862; COSMIC: COSV64474862;