rs17219315

Variant names:

• chr20-54171907-A-G
• rs17219315
• ENST00000395954.3:c.-214T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 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=-0.91).
• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.450-237T>C		intron_variant	Intron 2 of 11	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.450-237T>C		intron_variant	Intron 2 of 11	1	NM_000782.5	ENSP00000216862.3

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

African (AFR) AF: 0.00748 AC: 151 AN: 20184

American (AMR) AF: 0.0142 AC: 255 AN: 17922

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 375 AN: 14426

East Asian (EAS) AF: 0.0000393 AC: 1 AN: 25472

South Asian (SAS) AF: 0.0166 AC: 900 AN: 54348

European-Finnish (FIN) AF: 0.00370 AC: 76 AN: 20544

Middle Eastern (MID) AF: 0.0316 AC: 83 AN: 2624

European-Non Finnish (NFE) AF: 0.0237 AC: 16369 AN: 691762

Other (OTH) AF: 0.0246 AC: 922 AN: 37438

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

African (AFR) AF: 0.00722 AC: 300 AN: 41564

American (AMR) AF: 0.0184 AC: 281 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0156 AC: 75 AN: 4822

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1550 AN: 68036

Other (OTH) AF: 0.0227 AC: 48 AN: 2112

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.1
DANN	Benign	0.45
PhyloP100		0.27
PromoterAI		0.0026	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs17219315; hg19: chr20-52788446;