1-54886940-G-A

Position:

• chr1-54886940-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014762.4(DHCR24):​c.180C>T​(p.Leu60=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,608 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.018 (273 hom.)
• Consequence: DHCR24 NM_014762.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.34

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-54886940-G-A is Benign according to our data. Variant chr1-54886940-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 297664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1824/152330) while in subpopulation NFE AF= 0.0186 (1265/68024). AF 95% confidence interval is 0.0177. There are 12 homozygotes in gnomad4. There are 885 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR24	NM_014762.4	c.180C>T	p.Leu60=	synonymous_variant	1/9	ENST00000371269.9	NP_055577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR24	ENST00000371269.9	c.180C>T	p.Leu60=	synonymous_variant	1/9	1	NM_014762.4	ENSP00000360316	P1
	ENST00000689429.1	n.129G>A		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1826 AN: 152212 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0125 AC: 3120 AN: 249132 Hom.: 34 AF XY: 0.0130 AC XY: 1751 AN XY: 135138

Gnomad AFR exome AF: 0.00373

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00710

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0180 AC: 26343 AN: 1461278 Hom.: 273 Cov.: 34 AF XY: 0.0177 AC XY: 12873 AN XY: 726974

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00774

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0120 AC: 1824 AN: 152330 Hom.: 12 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74490

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.0163 Hom.: 15

Bravo AF: 0.0109

Asia WGS AF: 0.00202 AC: 8 AN: 3476

EpiCase AF: 0.0158

EpiControl AF: 0.0149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.84

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: rs79857573; hg19: chr1-55352613;