rs34578565

Variant names:

• chr15-74358739-C-G
• rs34578565
• NM_000781.3:c.269+8578G>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.269+8578G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 152,066 control chromosomes in the GnomAD database, including 19,083 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 0.47 (19083 hom., cov: 32)
• Consequence: CYP11A1 NM_000781.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.158
• Publications: 6 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

ENSG00000293337 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.269+8578G>C		intron_variant	Intron 1 of 8	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.-206+6977G>C		intron_variant	Intron 1 of 8		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.269+8578G>C		intron_variant	Intron 1 of 8	1	NM_000781.3	ENSP00000268053.6

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72048 AN: 151948 Hom.: 19085 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.474 AC: 72074 AN: 152066 Hom.: 19083 Cov.: 32 AF XY: 0.467 AC XY: 34755 AN XY: 74358

African (AFR) AF: 0.261 AC: 10819 AN: 41458

American (AMR) AF: 0.525 AC: 8027 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3472

East Asian (EAS) AF: 0.222 AC: 1151 AN: 5180

South Asian (SAS) AF: 0.264 AC: 1275 AN: 4822

European-Finnish (FIN) AF: 0.639 AC: 6763 AN: 10576

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

European-Non Finnish (NFE) AF: 0.603 AC: 40960 AN: 67952

Other (OTH) AF: 0.450 AC: 951 AN: 2112

Alfa AF: 0.548 Hom.: 3041

Bravo AF: 0.460

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.8
DANN	Benign	0.49
PhyloP100		0.16
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: rs34578565; hg19: chr15-74651080;