NM_003956.4:c.-44A>G

Variant names:

• chr10-89207336-T-C
• rs4417181
• NM_003956.4:c.-44A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003956.4(CH25H):​c.-44A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,430,892 control chromosomes in the GnomAD database, including 26,881 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 0.14 (3106 hom., cov: 32)
  • Exomes 𝑓: 0.15 (23775 hom.)
• Consequence: CH25H NM_003956.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• Publications: 9 publications found

Genes affected

CH25H (HGNC:1907): (cholesterol 25-hydroxylase) This is an intronless gene that is involved in cholesterol and lipid metabolism. The encoded protein is a membrane protein and contains clusters of histidine residues essential for catalytic activity. Unlike most other sterol hydroxylases, this enzyme is a member of a small family of enzymes that utilize diiron cofactors to catalyze the hydroxylation of hydrophobic substrates. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003956.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CH25H	NM_003956.4	MANE Select	c.-44A>G		upstream_gene	N/A	NP_003947.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CH25H	ENST00000371852.4	TSL:6 MANE Select	c.-44A>G		upstream_gene	N/A	ENSP00000360918.2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21832 AN: 152032 Hom.: 3095 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.243 AC: 28414 AN: 116766 AF XY: 0.242

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.750

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.150 AC: 191751 AN: 1278742 Hom.: 23775 Cov.: 19 AF XY: 0.155 AC XY: 97671 AN XY: 631234

African (AFR) AF: 0.0215 AC: 628 AN: 29266

American (AMR) AF: 0.287 AC: 9112 AN: 31748

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 3582 AN: 22072

East Asian (EAS) AF: 0.761 AC: 26573 AN: 34934

South Asian (SAS) AF: 0.292 AC: 21358 AN: 73128

European-Finnish (FIN) AF: 0.238 AC: 9732 AN: 40888

Middle Eastern (MID) AF: 0.151 AC: 563 AN: 3738

European-Non Finnish (NFE) AF: 0.112 AC: 111086 AN: 989516

Other (OTH) AF: 0.171 AC: 9117 AN: 53452

GnomAD4 genome AF: 0.144 AC: 21863 AN: 152150 Hom.: 3106 Cov.: 32 AF XY: 0.155 AC XY: 11550 AN XY: 74372

African (AFR) AF: 0.0267 AC: 1109 AN: 41552

American (AMR) AF: 0.221 AC: 3379 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 589 AN: 3470

East Asian (EAS) AF: 0.756 AC: 3900 AN: 5158

South Asian (SAS) AF: 0.325 AC: 1565 AN: 4818

European-Finnish (FIN) AF: 0.252 AC: 2662 AN: 10562

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8205 AN: 67986

Other (OTH) AF: 0.144 AC: 304 AN: 2110

Alfa AF: 0.122 Hom.: 894

Bravo AF: 0.139

Asia WGS AF: 0.456 AC: 1582 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.3
DANN	Benign	0.53
PhyloP100		0.26
PromoterAI		-0.056	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4417181; hg19: chr10-90967093;