rs35051736

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000782.5(CYP24A1):ā€‹c.470G>Cā€‹(p.Arg157Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R157Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

CYP24A1
NM_000782.5 missense

Scores

5
12
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.27
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-54171651-G-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP24A1NM_000782.5 linkuse as main transcriptc.470G>C p.Arg157Pro missense_variant 3/12 ENST00000216862.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP24A1ENST00000216862.8 linkuse as main transcriptc.470G>C p.Arg157Pro missense_variant 3/121 NM_000782.5 P1Q07973-1
CYP24A1ENST00000395955.7 linkuse as main transcriptc.470G>C p.Arg157Pro missense_variant 3/111 Q07973-2
CYP24A1ENST00000395954.3 linkuse as main transcriptc.44G>C p.Arg15Pro missense_variant 1/101 Q07973-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251282
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135808
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461682
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.71
D;.;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.86
D;D;D
MetaSVM
Uncertain
0.16
D
MutationAssessor
Pathogenic
3.0
M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.011
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
0.11
B;.;.
Vest4
0.94
MutPred
0.56
Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);.;
MVP
0.85
MPC
0.091
ClinPred
0.99
D
GERP RS
4.4
Varity_R
0.98
gMVP
0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35051736; hg19: chr20-52788189; API