Variant 14-99691808-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006668.2(CYP46A1):c.229G>T(p.Val77Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYP46A1
NM_006668.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Variant links:

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]

CYP46A1 links:

ENSG00000258672 (HGNC:):

ENSG00000258672 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP46A1	NM_006668.2 link	c.229G>T	p.Val77Phe	missense_variant	3/15	ENST00000261835.8	NP_006659.1	Q9Y6A2-1
CYP46A1	XM_011536364.2 link	c.229G>T	p.Val77Phe	missense_variant	3/15		XP_011534666.1
CYP46A1	XM_017020933.3 link	c.72G>T	p.Gly24Gly	synonymous_variant	3/16		XP_016876422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CYP46A1	ENST00000261835.8 link	c.229G>T	p.Val77Phe	missense_variant	3/15	1	NM_006668.2	ENSP00000261835.3	Q9Y6A2-1
CYP46A1	ENST00000554611.5 link	n.229G>T		non_coding_transcript_exon_variant	3/8	1		ENSP00000451069.1	G3V366
CYP46A1	ENST00000380228 link	c.-63G>T		5_prime_UTR_variant	3/15	2		ENSP00000369577.3	Q9Y6A2-2
ENSG00000258672	ENST00000555875.1 link	n.130C>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.229G>T (p.V77F) alteration is located in exon 3 (coding exon 3) of the CYP46A1 gene. This alteration results from a G to T substitution at nucleotide position 229, causing the valine (V) at amino acid position 77 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.82

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.18

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.77

REVEL

Uncertain

0.31

Sift

Benign

0.23

Sift4G

Benign

0.070

Polyphen

0.17

Vest4

0.81

MutPred

0.74

Gain of methylation at R76 (P = 0.1075);

MVP

0.95

MPC

1.4

ClinPred

0.34

GERP RS

3.4

Varity_R

0.38

gMVP

0.74

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over