20-54171650-C-T

Position:

chr20-54171650-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_000782.5(CYP24A1):c.470G>A(p.Arg157Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,613,850 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R157W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 61 hom. )

Consequence

CYP24A1
NM_000782.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

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]

CYP24A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-54171651-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.01509133).

BP6

Variant 20-54171650-C-T is Benign according to our data. Variant chr20-54171650-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 634948.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP24A1	NM_000782.5 linkuse as main transcript	c.470G>A	p.Arg157Gln	missense_variant	3/12	ENST00000216862.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP24A1	ENST00000216862.8 linkuse as main transcript	c.470G>A	p.Arg157Gln	missense_variant	3/12	1	NM_000782.5	P1	Q07973-1
CYP24A1	ENST00000395955.7 linkuse as main transcript	c.470G>A	p.Arg157Gln	missense_variant	3/11	1			Q07973-2
CYP24A1	ENST00000395954.3 linkuse as main transcript	c.44G>A	p.Arg15Gln	missense_variant	1/10	1			Q07973-3

Frequencies

GnomAD3 genomes

AF:

0.00368

AC:

560

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00296

AC:

744

AN:

251282

Hom.:

AF XY:

0.00297

AC XY:

403

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00653

AC:

9546

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00620

AC XY:

4505

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00806

Gnomad4 OTH exome

AF:

0.00659

GnomAD4 genome

AF:

0.00368

AC:

560

AN:

152168

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

251

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00145

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00703

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00580

Hom.:

Bravo

AF:

0.00352

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00251

AC:

305

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jan 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2020	See Variant Classification Assertion Criteria. -

Hypercalcemia, infantile, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

CYP24A1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.084

T;T;T

Polyphen

0.72

P;.;.

Vest4

0.86

MVP

0.78

MPC

0.11

ClinPred

0.023

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.47

gMVP

0.81

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over