rs8990

Positions:

• chr1-54850745-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014762.4(DHCR24):​c.*1488C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 152,268 control chromosomes in the GnomAD database, including 541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (540 hom., cov: 32)
  • Exomes 𝑓: 0.23 (1 hom.)
• Consequence: DHCR24 NM_014762.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-54850745-G-A is Benign according to our data. Variant chr1-54850745-G-A is described in ClinVar as [Benign]. Clinvar id is 297627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR24	NM_014762.4	c.*1488C>T		3_prime_UTR_variant	9/9	ENST00000371269.9	NP_055577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR24	ENST00000371269.9	c.*1488C>T		3_prime_UTR_variant	9/9	1	NM_014762.4	ENSP00000360316	P1

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11797 AN: 152124 Hom.: 539 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.0616

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0949

Gnomad OTH AF: 0.0717

GnomAD4 exome AF: 0.231 AC: 6 AN: 26 Hom.: 1 Cov.: 0 AF XY: 0.200 AC XY: 4 AN XY: 20

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0775 AC: 11800 AN: 152242 Hom.: 540 Cov.: 32 AF XY: 0.0746 AC XY: 5550 AN XY: 74432

Gnomad4 AFR AF: 0.0530

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.0679

Gnomad4 FIN AF: 0.0616

Gnomad4 NFE AF: 0.0949

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0869 Hom.: 132

Bravo AF: 0.0834

Asia WGS AF: 0.0410 AC: 144 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmosterolosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.36
DANN	Benign	0.70

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

Other links and lift over

dbSNP: rs8990; hg19: chr1-55316418;