1-54850268-G-T

Variant names:

• chr1-54850268-G-T
• rs11555500
• NM_014762.4:c.*1965C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014762.4(DHCR24):​c.*1965C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 152,316 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (75 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DHCR24 NM_014762.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.867
• Publications: 3 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=-0.83).
• BP6: Variant 1-54850268-G-T is Benign according to our data. Variant chr1-54850268-G-T is described in ClinVar as [Benign]. Clinvar id is 297621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0239 (3636/152316) while in subpopulation NFE AF = 0.0389 (2644/68028). AF 95% confidence interval is 0.0376. There are 75 homozygotes in GnomAd4. There are 1669 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 75 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR24	NM_014762.4	c.*1965C>A		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.*1965C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_014762.4	ENSP00000360316.3

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3636 AN: 152198 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0253

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12

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

GnomAD4 genome AF: 0.0239 AC: 3636 AN: 152316 Hom.: 75 Cov.: 33 AF XY: 0.0224 AC XY: 1669 AN XY: 74472

African (AFR) AF: 0.00712 AC: 296 AN: 41562

American (AMR) AF: 0.0146 AC: 223 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0389 AC: 2644 AN: 68028

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0325 Hom.: 140

Bravo AF: 0.0234

Asia WGS AF: 0.00202 AC: 8 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	-0.83
CADD	Benign	6.5
DANN	Benign	0.77
PhyloP100		0.87
Mutation Taster		=100/0	polymorphism

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: rs11555500; hg19: chr1-55315941;