6-32041310-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001365276.2(TNXB):c.*39G>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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (2 hom., cov: 23)
  • Exomes 𝑓: 0.024 (23 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.189

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-32041310-C-T is Benign according to our data. Variant chr6-32041310-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32041310-C-T is described in Lovd as [Likely_benign]. Variant chr6-32041310-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*176C>T		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.*39G>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.*176C>T		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.*39G>A		3_prime_UTR_variant	44/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2626 AN: 147624 Hom.: 2 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00463

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.00976

Gnomad EAS AF: 0.00362

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0245

GnomAD3 exomes AF: 0.0207 AC: 2995 AN: 144950 Hom.: 14 AF XY: 0.0222 AC XY: 1734 AN XY: 78120

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.00846

Gnomad EAS exome AF: 0.00421

Gnomad SAS exome AF: 0.0252

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0185

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0240 AC: 15183 AN: 633796 Hom.: 23 Cov.: 8 AF XY: 0.0242 AC XY: 8160 AN XY: 336810

Gnomad4 AFR exome AF: 0.00301

Gnomad4 AMR exome AF: 0.0153

Gnomad4 ASJ exome AF: 0.00806

Gnomad4 EAS exome AF: 0.00524

Gnomad4 SAS exome AF: 0.0252

Gnomad4 FIN exome AF: 0.0346

Gnomad4 NFE exome AF: 0.0269

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0178 AC: 2625 AN: 147742 Hom.: 2 Cov.: 23 AF XY: 0.0179 AC XY: 1287 AN XY: 71956

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.00976

Gnomad4 EAS AF: 0.00363

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.0243

Alfa AF: 0.0187 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	11
Dann	Benign	0.88

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: rs562025438; hg19: chr6-32009087;