6-32041190-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001365276.2(TNXB):c.*159G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,058,822 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 24)
  • Exomes 𝑓: 0.00057 (3 hom.)
• Consequence: TNXB NM_001365276.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.973

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32041190-C-G is Benign according to our data. Variant chr6-32041190-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1206744.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*56C>G		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.*159G>C		3_prime_UTR_variant	44/44	ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*56C>G		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.*159G>C		3_prime_UTR_variant	44/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 564 AN: 150518 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000742

Gnomad OTH AF: 0.00242

GnomAD4 exome AF: 0.000567 AC: 515 AN: 908190 Hom.: 3 Cov.: 14 AF XY: 0.000490 AC XY: 231 AN XY: 471280

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000146

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.00375 AC: 565 AN: 150632 Hom.: 3 Cov.: 24 AF XY: 0.00367 AC XY: 270 AN XY: 73560

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000742

Gnomad4 OTH AF: 0.00240

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	10
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs564636162; hg19: chr6-32008967;