6-32041186-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001365276.2(TNXB):c.*163G>A variant causes a 3 prime UTR 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (7942 hom., cov: 30)
  • Exomes 𝑓: 0.52 (88430 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.598

Genes affected

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]

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-32041186-C-T is Benign according to our data. Variant chr6-32041186-C-T is described in ClinVar as [Benign]. Clinvar id is 1235972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32041186-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 24735 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*52C>T		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.*163G>A		3_prime_UTR_variant	44/44	ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*52C>T		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.*163G>A		3_prime_UTR_variant	44/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 66839 AN: 139246 Hom.: 7933 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.471

GnomAD3 exomes AF: 0.549 AC: 116970 AN: 213094 Hom.: 24735 AF XY: 0.548 AC XY: 63993 AN XY: 116866

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.598

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.614

Gnomad SAS exome AF: 0.495

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.527

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.520 AC: 555648 AN: 1068038 Hom.: 88430 Cov.: 17 AF XY: 0.520 AC XY: 283155 AN XY: 544548

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.568

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.550

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.527

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.480 AC: 66900 AN: 139354 Hom.: 7942 Cov.: 30 AF XY: 0.478 AC XY: 32401 AN XY: 67748

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.507

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.568

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.474

Alfa AF: 0.505 Hom.: 2069

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

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

Aug 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	8.0
Dann	Benign	0.86

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: rs1058152; hg19: chr6-32008963; COSMIC: COSV64479006; COSMIC: COSV64479006;