NM_000781.3:c.939C>T

Variant names:

• chr15-74343028-G-A
• rs4986873
• NM_000781.3:c.939C>T
• CYP11A1 p.Phe313Phe

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000781.3(CYP11A1):​c.939C>T​(p.Phe313Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,090 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 32)
  • Exomes 𝑓: 0.015 (194 hom.)
• Consequence: CYP11A1 NM_000781.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.44
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-74343028-G-A is Benign according to our data. Variant chr15-74343028-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0107 (1635/152264) while in subpopulation NFE AF = 0.0151 (1028/68008). AF 95% confidence interval is 0.0143. There are 14 homozygotes in GnomAd4. There are 824 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11A1	NM_000781.3	MANE Select	c.939C>T	p.Phe313Phe	synonymous	Exon 5 of 9	NP_000772.2	P05108-1
	CYP11A1	NM_001099773.2		c.465C>T	p.Phe155Phe	synonymous	Exon 5 of 9	NP_001093243.1	P05108-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11A1	ENST00000268053.11	TSL:1 MANE Select	c.939C>T	p.Phe313Phe	synonymous	Exon 5 of 9	ENSP00000268053.6	P05108-1
	CYP11A1	ENST00000950903.1		c.939C>T	p.Phe313Phe	synonymous	Exon 5 of 10	ENSP00000620962.1
	CYP11A1	ENST00000950905.1		c.939C>T	p.Phe313Phe	synonymous	Exon 5 of 9	ENSP00000620964.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1634 AN: 152146 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.0110 AC: 2754 AN: 251436 AF XY: 0.0109

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.00879

GnomAD4 exome AF: 0.0148 AC: 21621 AN: 1460826 Hom.: 194 Cov.: 32 AF XY: 0.0144 AC XY: 10435 AN XY: 726750

African (AFR) AF: 0.00176 AC: 59 AN: 33440

American (AMR) AF: 0.00427 AC: 191 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00676 AC: 583 AN: 86204

European-Finnish (FIN) AF: 0.0301 AC: 1605 AN: 53394

Middle Eastern (MID) AF: 0.00161 AC: 8 AN: 4968

European-Non Finnish (NFE) AF: 0.0167 AC: 18556 AN: 1111950

Other (OTH) AF: 0.00990 AC: 597 AN: 60310

GnomAD4 genome AF: 0.0107 AC: 1635 AN: 152264 Hom.: 14 Cov.: 32 AF XY: 0.0111 AC XY: 824 AN XY: 74440

African (AFR) AF: 0.00303 AC: 126 AN: 41556

American (AMR) AF: 0.00751 AC: 115 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.0303 AC: 321 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1028 AN: 68008

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.0137 Hom.: 64

Bravo AF: 0.00918

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0128

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.29
DANN	Benign	0.54
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4986873;

hg19: chr15-74635369;