NM_000781.3:c.991-268G>A

Variant names:

• chr15-74340021-C-T
• rs7173655
• NM_000781.3:c.991-268G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000781.3(CYP11A1):​c.991-268G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 152,050 control chromosomes in the GnomAD database, including 22,693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.52 (22693 hom., cov: 32)
• Consequence: CYP11A1 NM_000781.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0330
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-74340021-C-T is Benign according to our data. Variant chr15-74340021-C-T is described in ClinVar as Benign. ClinVar VariationId is 1276272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.668 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.991-268G>A		intron	N/A	NP_000772.2
	CYP11A1	NM_001099773.2		c.517-268G>A		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.991-268G>A		intron	N/A	ENSP00000268053.6
	CYP11A1	ENST00000358632.8	TSL:2	c.517-268G>A		intron	N/A	ENSP00000351455.4
	CYP11A1	ENST00000566674.5	TSL:5	c.517-268G>A		intron	N/A	ENSP00000456941.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78764 AN: 151932 Hom.: 22695 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.680

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.497

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

GnomAD4 genome AF: 0.518 AC: 78782 AN: 152050 Hom.: 22693 Cov.: 32 AF XY: 0.510 AC XY: 37945 AN XY: 74334

African (AFR) AF: 0.292 AC: 12116 AN: 41458

American (AMR) AF: 0.403 AC: 6164 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2059 AN: 3470

East Asian (EAS) AF: 0.357 AC: 1848 AN: 5178

South Asian (SAS) AF: 0.438 AC: 2108 AN: 4818

European-Finnish (FIN) AF: 0.680 AC: 7193 AN: 10572

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.673 AC: 45759 AN: 67966

Other (OTH) AF: 0.492 AC: 1039 AN: 2110

Alfa AF: 0.584 Hom.: 3511

Bravo AF: 0.489

Asia WGS AF: 0.371 AC: 1290 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 09, 2018

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	-0.82
CADD	Benign	5.6
DANN	Benign	0.56
PhyloP100		-0.033
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: rs7173655; hg19: chr15-74632362;