14-99684108-G-A

Variant names:

• chr14-99684108-G-A
• rs7157609
• NM_006668.2:c.-310G>A

Variant summary

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

The NM_006668.2(CYP46A1):​c.-310G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 145,408 control chromosomes in the GnomAD database, including 5,930 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 0.27 (5930 hom., cov: 23)
• Consequence: CYP46A1 NM_006668.2 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 8 publications found

Genes affected

CYP46A1 (HGNC:2641): (cytochrome P450 family 46 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein is expressed in the brain, where it converts cholesterol to 24S-hydroxycholesterol. While cholesterol cannot pass the blood-brain barrier, 24S-hydroxycholesterol can be secreted in the brain into the circulation to be returned to the liver for catabolism. [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=-0.77).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP46A1	NM_006668.2	c.-310G>A		upstream_gene_variant		ENST00000261835.8	NP_006659.1
CYP46A1	XM_011536364.2	c.-310G>A		upstream_gene_variant			XP_011534666.1
CYP46A1	XM_017020933.3	c.-467G>A		upstream_gene_variant			XP_016876422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP46A1	ENST00000261835.8	c.-310G>A		upstream_gene_variant		1	NM_006668.2	ENSP00000261835.3
CYP46A1	ENST00000554611.5	n.-310G>A		upstream_gene_variant		1		ENSP00000451069.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 39454 AN: 145298 Hom.: 5930 Cov.: 23

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.276

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.254

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.271 AC: 39456 AN: 145408 Hom.: 5930 Cov.: 23 AF XY: 0.274 AC XY: 19368 AN XY: 70634

African (AFR) AF: 0.127 AC: 5012 AN: 39416

American (AMR) AF: 0.346 AC: 5061 AN: 14622

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 972 AN: 3412

East Asian (EAS) AF: 0.342 AC: 1620 AN: 4734

South Asian (SAS) AF: 0.380 AC: 1732 AN: 4558

European-Finnish (FIN) AF: 0.323 AC: 3029 AN: 9374

Middle Eastern (MID) AF: 0.273 AC: 77 AN: 282

European-Non Finnish (NFE) AF: 0.321 AC: 21224 AN: 66140

Other (OTH) AF: 0.257 AC: 514 AN: 2002

Alfa AF: 0.282 Hom.: 1699

Bravo AF: 0.264

Asia WGS AF: 0.357 AC: 1244 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.4
DANN	Benign	0.74
PhyloP100		-1.4
PromoterAI		-0.040	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7157609; hg19: chr14-100150445;