rs121912812

Positions:

chr15-74339668-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3PP5_Moderate

The NM_000781.3(CYP11A1):c.1076C>T(p.Ala359Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,882 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CYP11A1
NM_000781.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.17

Variant links:

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]

CYP11A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.745

PP5

Variant 15-74339668-G-A is Pathogenic according to our data. Variant chr15-74339668-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17520.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-74339668-G-A is described in UniProt as null. Variant chr15-74339668-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11A1	NM_000781.3 linkuse as main transcript	c.1076C>T	p.Ala359Val	missense_variant	6/9	ENST00000268053.11	NP_000772.2	P05108-1A0A0S2Z3R3
CYP11A1	NM_001099773.2 linkuse as main transcript	c.602C>T	p.Ala201Val	missense_variant	6/9		NP_001093243.1	P05108-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CYP11A1	ENST00000268053.11 linkuse as main transcript	c.1076C>T	p.Ala359Val	missense_variant	6/9	1	NM_000781.3	ENSP00000268053.6	P05108-1
CYP11A1	ENST00000358632.8 linkuse as main transcript	c.602C>T	p.Ala201Val	missense_variant	6/9	2		ENSP00000351455.4	P05108-2
CYP11A1	ENST00000566674.5 linkuse as main transcript	c.602C>T	p.Ala201Val	missense_variant	6/6	5		ENSP00000456941.1	H3BSZ1
CYP11A1	ENST00000435365.5 linkuse as main transcript	n.1076C>T		non_coding_transcript_exon_variant	6/8	3		ENSP00000391081.1	E7EPP8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251330

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727244

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000363

Hom.:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

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

Aug 01, 2006

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 21880796, 16705068, 19116240, 21159840, 18182448, 27855232, 37151110, 23337730, 26300845) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

.;T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.74

D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.5

.;L;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.52

Sift

Benign

0.033

D;D;T

Sift4G

Benign

0.47

T;T;.

Polyphen

1.0

.;D;.

Vest4

0.88

MVP

0.92

MPC

1.1

ClinPred

0.87

GERP RS

4.5

Varity_R

0.91

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over