Genetic Variant CYP11A1:c.1435-179A>C (chr15-74338282-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000781.3(CYP11A1):c.1435-179A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 607,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 31)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

CYP11A1
NM_000781.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.134

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP11A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3 link	c.1435-179A>C		intron_variant	Intron 8 of 8	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2 link	c.961-179A>C		intron_variant	Intron 8 of 8		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CYP11A1	ENST00000268053.11 link	c.1435-179A>C	intron_variant	Intron 8 of 8	1	NM_000781.3	ENSP00000268053.6
CYP11A1	ENST00000358632.8 link	c.961-179A>C	intron_variant	Intron 8 of 8	2		ENSP00000351455.4
CYP11A1	ENST00000435365.5 link	n.*111-179A>C	intron_variant	Intron 7 of 7	3		ENSP00000391081.1
CYP11A1	ENST00000498141.1 link	n.528+38A>C	intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000165

AC:

AN:

607672

Hom.:

Cov.:

AF XY:

0.00000312

AC XY:

AN XY:

320752

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

16622

American (AMR)

AF:

0.00

AC:

AN:

32514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17844

East Asian (EAS)

AF:

0.00

AC:

AN:

32208

South Asian (SAS)

AF:

0.00

AC:

AN:

57956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2496

European-Non Finnish (NFE)

AF:

0.00000262

AC:

AN:

381558

Other (OTH)

AF:

0.00

AC:

AN:

31812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.7

(source)

DANN

Benign

0.50

PhyloP100

-0.13

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over