rs72547508

Positions:

• chr15-74339687-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PP3_Strong PP5_Moderate

The NM_000781.3(CYP11A1):​c.1057C>T​(p.Arg353Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,950 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R353Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CYP11A1 NM_000781.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.73

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 16) in uniprot entity CP11A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000781.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 15-74339687-G-A is Pathogenic according to our data. Variant chr15-74339687-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17517.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-74339687-G-A is described in UniProt as null. Variant chr15-74339687-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11A1	NM_000781.3	c.1057C>T	p.Arg353Trp	missense_variant	6/9	ENST00000268053.11
CYP11A1	NM_001099773.2	c.583C>T	p.Arg195Trp	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11A1	ENST00000268053.11	c.1057C>T	p.Arg353Trp	missense_variant	6/9	1	NM_000781.3	P1
CYP11A1	ENST00000358632.8	c.583C>T	p.Arg195Trp	missense_variant	6/9	2
CYP11A1	ENST00000566674.5	c.583C>T	p.Arg195Trp	missense_variant	6/6	5
CYP11A1	ENST00000435365.5	c.1057C>T	p.Arg353Trp	missense_variant, NMD_transcript_variant	6/8	3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251368 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000274 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 30, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.96
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.98
gMVP		0.83

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: rs72547508; hg19: chr15-74632028;