rs718265

Variant names:

• chr1-54854229-A-G
• rs718265
• NM_014762.4:c.1026T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014762.4(DHCR24):​c.1026T>C​(p.Ile342Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 1,612,104 control chromosomes in the GnomAD database, including 385,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33909 hom., cov: 32)
  • Exomes 𝑓: 0.69 (351153 hom.)
• Consequence: DHCR24 NM_014762.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.67
• Publications: 34 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-54854229-A-G is Benign according to our data. Variant chr1-54854229-A-G is described in ClinVar as Benign. ClinVar VariationId is 297654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014762.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR24	NM_014762.4	MANE Select	c.1026T>C	p.Ile342Ile	synonymous	Exon 7 of 9	NP_055577.1	Q15392-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR24	ENST00000371269.9	TSL:1 MANE Select	c.1026T>C	p.Ile342Ile	synonymous	Exon 7 of 9	ENSP00000360316.3	Q15392-1
	DHCR24	ENST00000535035.6	TSL:1	c.1062T>C	p.Ile354Ile	synonymous	Exon 8 of 10	ENSP00000440191.3	A0A0A0MTI1
	DHCR24	ENST00000907938.1		c.1062T>C	p.Ile354Ile	synonymous	Exon 7 of 9	ENSP00000577997.1

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100905 AN: 151792 Hom.: 33896 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.653

GnomAD2 exomes AF: 0.662 AC: 164898 AN: 249076 AF XY: 0.677

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.398

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.691

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.691 AC: 1008540 AN: 1460194 Hom.: 351153 Cov.: 42 AF XY: 0.695 AC XY: 504600 AN XY: 726340

African (AFR) AF: 0.614 AC: 20560 AN: 33462

American (AMR) AF: 0.550 AC: 24543 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 18213 AN: 26076

East Asian (EAS) AF: 0.446 AC: 17682 AN: 39682

South Asian (SAS) AF: 0.800 AC: 68905 AN: 86106

European-Finnish (FIN) AF: 0.744 AC: 39638 AN: 53282

Middle Eastern (MID) AF: 0.624 AC: 3596 AN: 5764

European-Non Finnish (NFE) AF: 0.697 AC: 774699 AN: 1110862

Other (OTH) AF: 0.675 AC: 40704 AN: 60332

GnomAD4 genome AF: 0.665 AC: 100966 AN: 151910 Hom.: 33909 Cov.: 32 AF XY: 0.670 AC XY: 49757 AN XY: 74244

African (AFR) AF: 0.617 AC: 25528 AN: 41366

American (AMR) AF: 0.620 AC: 9467 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2404 AN: 3468

East Asian (EAS) AF: 0.411 AC: 2113 AN: 5138

South Asian (SAS) AF: 0.803 AC: 3876 AN: 4824

European-Finnish (FIN) AF: 0.756 AC: 7995 AN: 10572

Middle Eastern (MID) AF: 0.603 AC: 176 AN: 292

European-Non Finnish (NFE) AF: 0.697 AC: 47363 AN: 67962

Other (OTH) AF: 0.656 AC: 1382 AN: 2108

Alfa AF: 0.675 Hom.: 161850

Bravo AF: 0.639

Asia WGS AF: 0.603 AC: 2102 AN: 3478

EpiCase AF: 0.685

EpiControl AF: 0.685

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Desmosterolosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.7
Mutation Taster		=92/8	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: rs718265; hg19: chr1-55319902; COSMIC: COSV64875204; COSMIC: COSV64875204;