1-54849938-C-G

Variant names:

• chr1-54849938-C-G
• rs7373
• NM_014762.4:c.*2295G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014762.4(DHCR24):​c.*2295G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,478 control chromosomes in the GnomAD database, including 13,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13173 hom., cov: 33)
  • Exomes 𝑓: 0.26 (15 hom.)
• Consequence: DHCR24 NM_014762.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.54
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-54849938-C-G is Benign according to our data. Variant chr1-54849938-C-G is described in ClinVar as [Benign]. Clinvar id is 297617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR24	NM_014762.4	c.*2295G>C		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.*2295G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_014762.4	ENSP00000360316.3

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59729 AN: 151968 Hom.: 13146 Cov.: 33

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.384

GnomAD4 exome AF: 0.259 AC: 101 AN: 390 Hom.: 15 Cov.: 0 AF XY: 0.252 AC XY: 63 AN XY: 250

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.240 AC: 87 AN: 362

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.650 AC: 13 AN: 20

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.393 AC: 59822 AN: 152088 Hom.: 13173 Cov.: 33 AF XY: 0.386 AC XY: 28735 AN XY: 74350

African (AFR) AF: 0.582 AC: 24135 AN: 41444

American (AMR) AF: 0.403 AC: 6161 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1074 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3048 AN: 5168

South Asian (SAS) AF: 0.198 AC: 956 AN: 4828

European-Finnish (FIN) AF: 0.247 AC: 2621 AN: 10592

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20651 AN: 67984

Other (OTH) AF: 0.381 AC: 806 AN: 2114

Alfa AF: 0.343 Hom.: 1283

Bravo AF: 0.426

Asia WGS AF: 0.404 AC: 1403 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmosterolosis Benign:1

Jan 12, 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	-0.76
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		1.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
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: rs7373; hg19: chr1-55315611;