15-74345526-A-G

Variant names:

• chr15-74345526-A-G
• rs11632698
• NM_000781.3:c.426-283T>C

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.426-283T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 151,646 control chromosomes in the GnomAD database, including 19,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.48 (19189 hom., cov: 31)
• Consequence: CYP11A1 NM_000781.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.400
• Publications: 25 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=-0.88).
• BP6: Variant 15-74345526-A-G is Benign according to our data. Variant chr15-74345526-A-G is described in ClinVar as Benign. ClinVar VariationId is 1276338.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000781.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11A1	NM_000781.3	MANE Select	c.426-283T>C		intron	N/A	NP_000772.2
	CYP11A1	NM_001099773.2		c.-49-283T>C		intron	N/A	NP_001093243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11A1	ENST00000268053.11	TSL:1 MANE Select	c.426-283T>C		intron	N/A	ENSP00000268053.6
	CYP11A1	ENST00000358632.8	TSL:2	c.-49-283T>C		intron	N/A	ENSP00000351455.4
	CYP11A1	ENST00000566674.5	TSL:5	c.-49-283T>C		intron	N/A	ENSP00000456941.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72175 AN: 151528 Hom.: 19191 Cov.: 31

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.460

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

GnomAD4 genome AF: 0.476 AC: 72201 AN: 151646 Hom.: 19189 Cov.: 31 AF XY: 0.470 AC XY: 34796 AN XY: 74108

African (AFR) AF: 0.262 AC: 10813 AN: 41280

American (AMR) AF: 0.526 AC: 8023 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 1738 AN: 3464

East Asian (EAS) AF: 0.221 AC: 1136 AN: 5132

South Asian (SAS) AF: 0.267 AC: 1276 AN: 4782

European-Finnish (FIN) AF: 0.642 AC: 6753 AN: 10524

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41118 AN: 67906

Other (OTH) AF: 0.455 AC: 955 AN: 2098

Alfa AF: 0.556 Hom.: 105924

Bravo AF: 0.461

Asia WGS AF: 0.235 AC: 818 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.93
DANN	Benign	0.66
PhyloP100		-0.40
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: rs11632698; hg19: chr15-74637867;