rs17219315

Positions:

• chr20-54171907-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000395954.3(CYP24A1):​c.-214T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,037,038 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 32)
  • Exomes 𝑓: 0.022 (229 hom.)
• Consequence: CYP24A1 ENST00000395954.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.274

Genes affected

CYP24A1 (HGNC:2602): (cytochrome P450 family 24 subfamily A member 1) 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 mitochondrial protein initiates the degradation of 1,25-dihydroxyvitamin D3, the physiologically active form of vitamin D3, by hydroxylation of the side chain. In regulating the level of vitamin D3, this enzyme plays a role in calcium homeostasis and the vitamin D endocrine system. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-54171907-A-G is Benign according to our data. Variant chr20-54171907-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1187714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2461/152318) while in subpopulation NFE AF= 0.0228 (1550/68036). AF 95% confidence interval is 0.0218. There are 28 homozygotes in gnomad4. There are 1113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.450-237T>C		intron_variant		ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000395954.3	c.-214T>C		5_prime_UTR_premature_start_codon_gain_variant	1/10	1		ENSP00000379284.3
CYP24A1	ENST00000395954.3	c.-214T>C		5_prime_UTR_variant	1/10	1		ENSP00000379284.3
CYP24A1	ENST00000216862.8	c.450-237T>C		intron_variant		1	NM_000782.5	ENSP00000216862.3
CYP24A1	ENST00000395955.7	c.450-237T>C		intron_variant		1		ENSP00000379285.3

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2448 AN: 152202 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0216 AC: 19132 AN: 884720 Hom.: 229 Cov.: 12 AF XY: 0.0216 AC XY: 9495 AN XY: 440216

Gnomad4 AFR exome AF: 0.00748

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.0000393

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.00370

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0246

GnomAD4 genome AF: 0.0162 AC: 2461 AN: 152318 Hom.: 28 Cov.: 32 AF XY: 0.0149 AC XY: 1113 AN XY: 74480

Gnomad4 AFR AF: 0.00722

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0206 Hom.: 15

Bravo AF: 0.0174

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

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	Aug 20, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.1
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17219315; hg19: chr20-52788446;