rs4809957

Variant names:

• chr20-54154632-A-G
• rs4809957
• NM_000782.5:c.*140T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000782.5(CYP24A1):​c.*140T>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 0.291 in 155,000 control chromosomes in the GnomAD database, including 7,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7351 hom., cov: 31)
  • Exomes 𝑓: 0.27 (129 hom.)
• Consequence: CYP24A1 NM_000782.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.904
• Publications: 56 publications found

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]

CYP24A1 Gene-Disease associations (from GenCC):

• hypercalcemia, infantile, 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal recessive infantile hypercalcemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286587 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-54154632-A-G is Benign according to our data. Variant chr20-54154632-A-G is described in ClinVar as Benign. ClinVar VariationId is 338806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.*140T>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.*140T>C		3_prime_UTR_variant	Exon 12 of 12	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44191 AN: 151856 Hom.: 7344 Cov.: 31

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.269 AC: 814 AN: 3026 Hom.: 129 Cov.: 0 AF XY: 0.263 AC XY: 442 AN XY: 1678

African (AFR) AF: 0.382 AC: 29 AN: 76

American (AMR) AF: 0.333 AC: 24 AN: 72

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 22 AN: 84

East Asian (EAS) AF: 0.621 AC: 231 AN: 372

South Asian (SAS) AF: 0.313 AC: 5 AN: 16

European-Finnish (FIN) AF: 0.209 AC: 79 AN: 378

Middle Eastern (MID) AF: 0.250 AC: 3 AN: 12

European-Non Finnish (NFE) AF: 0.204 AC: 384 AN: 1884

Other (OTH) AF: 0.280 AC: 37 AN: 132

GnomAD4 genome AF: 0.291 AC: 44220 AN: 151974 Hom.: 7351 Cov.: 31 AF XY: 0.294 AC XY: 21815 AN XY: 74274

African (AFR) AF: 0.416 AC: 17240 AN: 41424

American (AMR) AF: 0.274 AC: 4185 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 795 AN: 3466

East Asian (EAS) AF: 0.607 AC: 3132 AN: 5164

South Asian (SAS) AF: 0.354 AC: 1706 AN: 4814

European-Finnish (FIN) AF: 0.204 AC: 2155 AN: 10568

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14260 AN: 67956

Other (OTH) AF: 0.262 AC: 554 AN: 2112

Alfa AF: 0.243 Hom.: 18756

Bravo AF: 0.301

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercalcemia, infantile, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.57
DANN	Benign	0.57
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4809957; hg19: chr20-52771171;