20-54171651-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000782.5(CYP24A1):c.469C>A(p.Arg157=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,613,754 control chromosomes in the GnomAD database, including 486 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: 0.023 (458 hom.)
• Consequence: CYP24A1 NM_000782.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.42

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 20-54171651-G-T is Benign according to our data. Variant chr20-54171651-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 895614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54171651-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2458/152092) while in subpopulation NFE AF= 0.0228 (1549/68004). AF 95% confidence interval is 0.0218. There are 28 homozygotes in gnomad4. There are 1110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP24A1	NM_000782.5	c.469C>A	p.Arg157=	synonymous_variant	3/12	ENST00000216862.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP24A1	ENST00000216862.8	c.469C>A	p.Arg157=	synonymous_variant	3/12	1	NM_000782.5	P1
CYP24A1	ENST00000395955.7	c.469C>A	p.Arg157=	synonymous_variant	3/11	1
CYP24A1	ENST00000395954.3	c.43C>A	p.Arg15=	synonymous_variant	1/10	1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2445 AN: 151974 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00699

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0163 AC: 4105 AN: 251288 Hom.: 54 AF XY: 0.0174 AC XY: 2357 AN XY: 135810

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0170

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0230 AC: 33549 AN: 1461662 Hom.: 458 Cov.: 33 AF XY: 0.0228 AC XY: 16601 AN XY: 727144

Gnomad4 AFR exome AF: 0.00807

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0295

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0177

Gnomad4 FIN exome AF: 0.00292

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.0253

GnomAD4 genome AF: 0.0162 AC: 2458 AN: 152092 Hom.: 28 Cov.: 32 AF XY: 0.0149 AC XY: 1110 AN XY: 74356

Gnomad4 AFR AF: 0.00726

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0154

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00644 Hom.: 76

Bravo AF: 0.0174

EpiCase AF: 0.0268

EpiControl AF: 0.0257

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CYP24A1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hypercalcemia, infantile, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 29, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	6.8
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35873579; hg19: chr20-52788190; COSMIC: COSV53775925; COSMIC: COSV53775925;