1-54886937-G-T

Variant names:

• chr1-54886937-G-T
• rs753821643
• NM_014762.4:c.183C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014762.4(DHCR24):​c.183C>A​(p.Ser61Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S61S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHCR24 NM_014762.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.31
• 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 2 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=0.3360662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR24	NM_014762.4	c.183C>A	p.Ser61Arg	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.183C>A	p.Ser61Arg	missense_variant	Exon 1 of 9	1	NM_014762.4	ENSP00000360316.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248850 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.24	T;T;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.068
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.55	N;N;.;N
PhyloP100		7.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.91	.;N;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.59	.;T;.;.
Sift4G	Benign	0.57	.;T;.;.
Polyphen		0.0010	B;B;.;B
Vest4		0.29
MutPred		0.51		Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);
MVP		0.47
MPC		1.3
ClinPred		0.20	T
GERP RS		5.3
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.78
Mutation Taster		=71/29	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: rs753821643; hg19: chr1-55352610;