15-74338065-G-T

Variant names:

• chr15-74338065-G-T
• rs764433725
• NM_000781.3:c.1473C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000781.3(CYP11A1):​c.1473C>A​(p.Ser491Arg) 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 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYP11A1 NM_000781.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.29

Genes affected

CYP11A1 (HGNC:2590): (cytochrome P450 family 11 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 protein localizes to the mitochondrial inner membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in the synthesis of the steroid hormones. Two transcript variants encoding different isoforms have been found for this gene. The cellular location of the smaller isoform is unclear since it lacks the mitochondrial-targeting transit peptide. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08058116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.1473C>A	p.Ser491Arg	missense_variant	Exon 9 of 9	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.999C>A	p.Ser333Arg	missense_variant	Exon 9 of 9		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.1473C>A	p.Ser491Arg	missense_variant	Exon 9 of 9	1	NM_000781.3	ENSP00000268053.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.0010
DANN	Benign	0.52
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.21	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	.;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.10
Sift	Benign	0.42	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0090	.;B
Vest4		0.067
MutPred		0.51		.;Gain of catalytic residue at S491 (P = 0.0966);
MVP		0.45
MPC		0.37
ClinPred		0.037	T
GERP RS		-9.9
Varity_R		0.22
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs764433725; hg19: chr15-74630406;