rs886041121

Positions:

• chr15-74342999-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000781.3(CYP11A1):​c.968T>A​(p.Met323Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP11A1 NM_000781.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.92

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 15-74342999-A-T is Pathogenic according to our data. Variant chr15-74342999-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280943.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.968T>A	p.Met323Lys	missense_variant	5/9	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.494T>A	p.Met165Lys	missense_variant	5/9		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.968T>A	p.Met323Lys	missense_variant	5/9	1	NM_000781.3	ENSP00000268053.6
CYP11A1	ENST00000358632.8	c.494T>A	p.Met165Lys	missense_variant	5/9	2		ENSP00000351455.4
CYP11A1	ENST00000566674.5	c.494T>A	p.Met165Lys	missense_variant	5/6	5		ENSP00000456941.1
CYP11A1	ENST00000435365.5	n.968T>A		non_coding_transcript_exon_variant	5/8	3		ENSP00000391081.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

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:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Apr 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	.;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Uncertain	2.6	.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.90	.;P;.
Vest4		0.82
MutPred		0.89		.;Gain of disorder (P = 0.0374);.;
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.98
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886041121; hg19: chr15-74635340;