ENST00000395954.3:c.25G>T

Variant names:

• chr20-54171669-C-A
• rs387907323
• ENST00000395954.3:c.25G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000395954.3(CYP24A1):​c.25G>T​(p.Glu9*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP24A1 ENST00000395954.3 stop_gained
• Scores: Splicing: ADA: 0.01029
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.27
• Publications: 2 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-54171669-C-A is Pathogenic according to our data. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-54171669-C-A is described in CliVar as Pathogenic. Clinvar id is 29678.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.451G>T	p.Glu151*	stop_gained, splice_region_variant	Exon 3 of 12	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.451G>T	p.Glu151*	stop_gained, splice_region_variant	Exon 3 of 12	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypercalcemia, infantile, 1 Pathogenic:1

Aug 04, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.3
Vest4		0.97
GERP RS		3.6
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.030		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: rs387907323; hg19: chr20-52788208;