rs8990

Variant names:

• chr1-54850745-G-A
• rs8990
• NM_014762.4:c.*1488C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 11 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 Gene-Disease associations (from GenCC):

• desmosterolosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• 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 rank	MANE	Protein	UniProt
DHCR24	NM_014762.4	c.*1488C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000371269.9	NP_055577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR24	ENST00000371269.9	c.*1488C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_014762.4	ENSP00000360316.3

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.300 AC: 6 AN: 20

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.040428), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0530 AC: 2202 AN: 41554

American (AMR) AF: 0.106 AC: 1615 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3468

East Asian (EAS) AF: 0.0104 AC: 54 AN: 5190

South Asian (SAS) AF: 0.0679 AC: 327 AN: 4818

European-Finnish (FIN) AF: 0.0616 AC: 653 AN: 10594

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0949 AC: 6454 AN: 68012

Other (OTH) AF: 0.0710 AC: 150 AN: 2114

Alfa AF: 0.0864 Hom.: 135

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.36
DANN	Benign	0.70
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs8990; hg19: chr1-55316418;