14-99691808-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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]

(HGNC:):

ACMG classification

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	UniProt
CYP46A1	NM_006668.2	c.229G>T	p.Val77Phe	missense_variant	3/15	ENST00000261835.8
CYP46A1	XM_011536364.2	c.229G>T	p.Val77Phe	missense_variant	3/15
CYP46A1	XM_017020933.3	c.72G>T	p.Gly24=	synonymous_variant	3/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP46A1	ENST00000261835.8	c.229G>T	p.Val77Phe	missense_variant	3/15	1	NM_006668.2	P1
	ENST00000555875.1	n.130C>A		non_coding_transcript_exon_variant	3/3	3
CYP46A1	ENST00000554611.5	c.229G>T	p.Val77Phe	missense_variant, NMD_transcript_variant	3/8	1
CYP46A1	ENST00000380228.6	c.-63G>T		5_prime_UTR_variant	3/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.18	N
MutationTaster	Benign	0.69	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.31
Sift	Benign	0.23	T
Sift4G	Benign	0.070	T
Polyphen		0.17	B
Vest4		0.81
MutPred		0.74		Gain of methylation at R76 (P = 0.1075);
MVP		0.95
MPC		1.4
ClinPred		0.34	T
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.

Other links and lift over

hg19: chr14-100158145;