rs1484215

Variant names:

• chr15-74347768-C-T
• rs1484215
• NM_000781.3:c.425+132G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000781.3(CYP11A1):​c.425+132G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0766 in 790,358 control chromosomes in the GnomAD database, including 3,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.062 (402 hom., cov: 32)
  • Exomes 𝑓: 0.080 (2742 hom.)
• Consequence: CYP11A1 NM_000781.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.63
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-74347768-C-T is Benign according to our data. Variant chr15-74347768-C-T is described in ClinVar as Benign. ClinVar VariationId is 1270755.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.425+132G>A		intron_variant	Intron 2 of 8	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.-50+132G>A		intron_variant	Intron 2 of 8		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.425+132G>A		intron_variant	Intron 2 of 8	1	NM_000781.3	ENSP00000268053.6

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9433 AN: 152080 Hom.: 403 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0604

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0709

GnomAD4 exome AF: 0.0801 AC: 51127 AN: 638160 Hom.: 2742 AF XY: 0.0856 AC XY: 28489 AN XY: 332992

African (AFR) AF: 0.0223 AC: 364 AN: 16290

American (AMR) AF: 0.0426 AC: 1064 AN: 24974

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 1458 AN: 17698

East Asian (EAS) AF: 0.166 AC: 5275 AN: 31826

South Asian (SAS) AF: 0.175 AC: 10179 AN: 58228

European-Finnish (FIN) AF: 0.0449 AC: 1882 AN: 41946

Middle Eastern (MID) AF: 0.136 AC: 337 AN: 2472

European-Non Finnish (NFE) AF: 0.0677 AC: 27939 AN: 412442

Other (OTH) AF: 0.0814 AC: 2629 AN: 32284

GnomAD4 genome AF: 0.0620 AC: 9431 AN: 152198 Hom.: 402 Cov.: 32 AF XY: 0.0644 AC XY: 4792 AN XY: 74410

African (AFR) AF: 0.0222 AC: 920 AN: 41530

American (AMR) AF: 0.0603 AC: 923 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3470

East Asian (EAS) AF: 0.183 AC: 948 AN: 5176

South Asian (SAS) AF: 0.171 AC: 823 AN: 4812

European-Finnish (FIN) AF: 0.0521 AC: 552 AN: 10600

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0689 AC: 4684 AN: 67988

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0673 Hom.: 989

Bravo AF: 0.0595

Asia WGS AF: 0.152 AC: 526 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.28
DANN	Benign	0.36
PhyloP100		-1.6
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: rs1484215; hg19: chr15-74640109;