rs121912813

Positions:

• chr15-74347903-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000268053.11(CYP11A1):​c.422T>G​(p.Leu141Trp) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP11A1 ENST00000268053.11 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 15-74347903-A-C is Pathogenic according to our data. Variant chr15-74347903-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17522.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-74347903-A-C is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.422T>G	p.Leu141Trp	missense_variant	2/9	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.-53T>G		5_prime_UTR_variant	2/9		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.422T>G	p.Leu141Trp	missense_variant	2/9	1	NM_000781.3	ENSP00000268053	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.91		Loss of stability (P = 0.0427);Loss of stability (P = 0.0427);
MVP		0.93
MPC		1.4
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.68
gMVP		0.81

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: rs121912813; hg19: chr15-74640244;