1-54887068-C-A

Variant names:

• chr1-54887068-C-A
• rs776065385
• NM_014762.4:c.52G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014762.4(DHCR24):​c.52G>T​(p.Val18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHCR24 NM_014762.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.405
• Publications: 0 publications found

Genes affected

DHCR24 (HGNC:2859): (24-dehydrocholesterol reductase) This gene encodes a flavin adenine dinucleotide (FAD)-dependent oxidoreductase which catalyzes the reduction of the delta-24 double bond of sterol intermediates during cholesterol biosynthesis. The protein contains a leader sequence that directs it to the endoplasmic reticulum membrane. Missense mutations in this gene have been associated with desmosterolosis. Also, reduced expression of the gene occurs in the temporal cortex of Alzheimer disease patients and overexpression has been observed in adrenal gland cancer cells. [provided by RefSeq, Jul 2008]

DHCR24-DT (HGNC:53969): (DHCR24 divergent transcript)

TMEM61 (HGNC:27296): (transmembrane protein 61) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.5014 (below the threshold of 3.09). Trascript score misZ: 2.3826 (below the threshold of 3.09). GenCC associations: The gene is linked to desmosterolosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1811913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR24	NM_014762.4	c.52G>T	p.Val18Leu	missense_variant	Exon 1 of 9	ENST00000371269.9	NP_055577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR24	ENST00000371269.9	c.52G>T	p.Val18Leu	missense_variant	Exon 1 of 9	1	NM_014762.4	ENSP00000360316.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with leucine at codon 18 of the DHCR24 protein (p.Val18Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DHCR24-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0067	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	.;.;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.6	L;L;.;L
PhyloP100		0.41
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.40	.;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.17	.;T;.;.
Sift4G	Benign	0.28	.;T;.;.
Polyphen		0.0010	B;B;.;B
Vest4		0.18
MutPred		0.27		Loss of ubiquitination at K21 (P = 0.1231);Loss of ubiquitination at K21 (P = 0.1231);Loss of ubiquitination at K21 (P = 0.1231);Loss of ubiquitination at K21 (P = 0.1231);
MVP		0.42
MPC		1.1
ClinPred		0.23	T
GERP RS		0.39
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.090
gMVP		0.42
Mutation Taster		=94/6	polymorphism

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: rs776065385; hg19: chr1-55352741;