Genetic Variant DHCR24:p.Ser6Trp (chr1-54887103-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_014762.4(DHCR24):c.17C>G(p.Ser6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S6L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

DHCR24
NM_014762.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.94

Publications

0 publications found

Variant links:

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 links:

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

DHCR24-DT links:

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

TMEM61 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR24	NM_014762.4 link	c.17C>G	p.Ser6Trp	missense_variant	Exon 1 of 9	ENST00000371269.9	NP_055577.1	Q15392-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR24	ENST00000371269.9 link	c.17C>G	p.Ser6Trp	missense_variant	Exon 1 of 9	1	NM_014762.4	ENSP00000360316.3		Q15392-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437692

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

40096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25640

East Asian (EAS)

AF:

0.00

AC:

AN:

38768

South Asian (SAS)

AF:

0.00

AC:

AN:

83530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1100862

Other (OTH)

AF:

0.00

AC:

AN:

59586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T;.;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

.;.;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.9

L;L;.;L

PhyloP100

2.9

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.46

.;N;.;.

REVEL

Uncertain

0.51

Sift

Benign

0.19

.;T;.;.

Sift4G

Benign

0.18

.;T;.;.

Polyphen

0.98

D;D;.;D

Vest4

0.67

MutPred

0.41

Loss of disorder (P = 0.0016);Loss of disorder (P = 0.0016);Loss of disorder (P = 0.0016);Loss of disorder (P = 0.0016);

MVP

0.70

MPC

2.2

ClinPred

0.96

GERP RS

4.9

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.74

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over