rs4900442

Variant names:

• chr14-99691904-C-T
• rs4900442
• NM_006668.2:c.282+43C>T

Variant summary

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

The NM_006668.2(CYP46A1):​c.282+43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,594,892 control chromosomes in the GnomAD database, including 172,128 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 0.43 (14655 hom., cov: 32)
  • Exomes 𝑓: 0.47 (157473 hom.)
• Consequence: CYP46A1 NM_006668.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.597
• Publications: 13 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]

ENSG00000258672 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP46A1	NM_006668.2	c.282+43C>T		intron_variant	Intron 3 of 14	ENST00000261835.8	NP_006659.1
CYP46A1	XM_011536364.2	c.282+43C>T		intron_variant	Intron 3 of 14		XP_011534666.1
CYP46A1	XM_017020933.3	c.125+43C>T		intron_variant	Intron 3 of 15		XP_016876422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP46A1	ENST00000261835.8	c.282+43C>T		intron_variant	Intron 3 of 14	1	NM_006668.2	ENSP00000261835.3
CYP46A1	ENST00000554611.5	n.282+43C>T		intron_variant	Intron 3 of 7	1		ENSP00000451069.1
CYP46A1	ENST00000380228.6	c.-10+43C>T		intron_variant	Intron 3 of 14	2		ENSP00000369577.3
ENSG00000258672	ENST00000555875.2	n.275-57G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65679 AN: 151802 Hom.: 14642 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.428

GnomAD2 exomes AF: 0.474 AC: 118829 AN: 250456 AF XY: 0.474

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.575

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.495

Gnomad FIN exome AF: 0.455

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.466 AC: 672386 AN: 1442972 Hom.: 157473 Cov.: 25 AF XY: 0.466 AC XY: 335025 AN XY: 718946

African (AFR) AF: 0.317 AC: 10471 AN: 33048

American (AMR) AF: 0.568 AC: 25345 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 11932 AN: 25998

East Asian (EAS) AF: 0.519 AC: 20528 AN: 39572

South Asian (SAS) AF: 0.493 AC: 42323 AN: 85844

European-Finnish (FIN) AF: 0.456 AC: 24322 AN: 53350

Middle Eastern (MID) AF: 0.433 AC: 2480 AN: 5730

European-Non Finnish (NFE) AF: 0.464 AC: 507619 AN: 1095052

Other (OTH) AF: 0.458 AC: 27366 AN: 59768

GnomAD4 genome AF: 0.433 AC: 65728 AN: 151920 Hom.: 14655 Cov.: 32 AF XY: 0.432 AC XY: 32108 AN XY: 74256

African (AFR) AF: 0.333 AC: 13801 AN: 41440

American (AMR) AF: 0.502 AC: 7673 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1590 AN: 3470

East Asian (EAS) AF: 0.494 AC: 2547 AN: 5158

South Asian (SAS) AF: 0.502 AC: 2409 AN: 4798

European-Finnish (FIN) AF: 0.446 AC: 4708 AN: 10554

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31470 AN: 67916

Other (OTH) AF: 0.434 AC: 916 AN: 2110

Alfa AF: 0.449 Hom.: 12029

Bravo AF: 0.432

Asia WGS AF: 0.500 AC: 1741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.75
PhyloP100		-0.60
Mutation Taster		=100/0	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: rs4900442; hg19: chr14-100158241;