chr15-74342558-C-G

Variant names:

• chr15-74342558-C-G
• rs11638442
• NM_000781.3:c.990+419G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000781.3(CYP11A1):​c.990+419G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 151,964 control chromosomes in the GnomAD database, including 19,353 homozygotes. 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: 𝑓 0.48 (19353 hom., cov: 31)
• Consequence: CYP11A1 NM_000781.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0470
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.990+419G>C		intron_variant	Intron 5 of 8	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.516+419G>C		intron_variant	Intron 5 of 8		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.990+419G>C		intron_variant	Intron 5 of 8	1	NM_000781.3	ENSP00000268053.6
CYP11A1	ENST00000358632.8	c.516+419G>C		intron_variant	Intron 5 of 8	2		ENSP00000351455.4
CYP11A1	ENST00000566674.5	c.516+419G>C		intron_variant	Intron 5 of 5	5		ENSP00000456941.1
CYP11A1	ENST00000435365.5	n.990+419G>C		intron_variant	Intron 5 of 7	3		ENSP00000391081.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72699 AN: 151846 Hom.: 19355 Cov.: 31

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.460

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.479 AC: 72727 AN: 151964 Hom.: 19353 Cov.: 31 AF XY: 0.472 AC XY: 35041 AN XY: 74286

African (AFR) AF: 0.273 AC: 11314 AN: 41422

American (AMR) AF: 0.527 AC: 8046 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1738 AN: 3470

East Asian (EAS) AF: 0.221 AC: 1140 AN: 5162

South Asian (SAS) AF: 0.266 AC: 1281 AN: 4808

European-Finnish (FIN) AF: 0.640 AC: 6763 AN: 10570

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41098 AN: 67946

Other (OTH) AF: 0.456 AC: 961 AN: 2108

Alfa AF: 0.437 Hom.: 1453

Bravo AF: 0.465

Asia WGS AF: 0.236 AC: 821 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.076
DANN	Benign	0.71
PhyloP100		-0.047
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11638442; hg19: chr15-74634899;