14-99699891-G-A

Position:

• chr14-99699891-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_006668.2(CYP46A1):​c.357-124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 669,090 control chromosomes in the GnomAD database, including 7,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (1736 hom., cov: 31)
  • Exomes 𝑓: 0.15 (6259 hom.)
• Consequence: CYP46A1 NM_006668.2 intron
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: -3.42

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 14-99699891-G-A is Benign according to our data. Variant chr14-99699891-G-A is described in ClinVar as [protective]. Clinvar id is 1693592.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_benign, oryginal submission is: [protective].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP46A1	NM_006668.2	c.357-124G>A		intron_variant		ENST00000261835.8	NP_006659.1
CYP46A1	XM_011536364.2	c.357-124G>A		intron_variant			XP_011534666.1
CYP46A1	XM_017020933.3	c.243-124G>A		intron_variant			XP_016876422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP46A1	ENST00000261835.8	c.357-124G>A		intron_variant		1	NM_006668.2	ENSP00000261835	P1
CYP46A1	ENST00000554611.5	c.*109-124G>A		intron_variant, NMD_transcript_variant		1		ENSP00000451069
CYP46A1	ENST00000380228.6	c.66-124G>A		intron_variant		2		ENSP00000369577

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23021 AN: 151942 Hom.: 1737 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.151 AC: 77817 AN: 517030 Hom.: 6259 AF XY: 0.151 AC XY: 40598 AN XY: 268860

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.152 AC: 23052 AN: 152060 Hom.: 1736 Cov.: 31 AF XY: 0.152 AC XY: 11266 AN XY: 74350

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.153

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.166

Alfa AF: 0.154 Hom.: 3871

Bravo AF: 0.152

Asia WGS AF: 0.158 AC: 546 AN: 3478

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary disease, chronic obstructive, susceptibility to Benign:1

protective, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 11, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs3742377; hg19: chr14-100166228; COSMIC: COSV55895729;