rs143655263

Positions:

• chr15-74367351-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000268053.11(CYP11A1):​c.235G>A​(p.Val79Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,614,158 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V79V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (24 hom.)
• Consequence: CYP11A1 ENST00000268053.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.83

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055402517).
• BP6: Variant 15-74367351-C-T is Benign according to our data. Variant chr15-74367351-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 317132.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=1}. Variant chr15-74367351-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00297 (453/152270) while in subpopulation NFE AF= 0.00529 (360/68030). AF 95% confidence interval is 0.00484. There are 1 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.235G>A	p.Val79Ile	missense_variant	1/9	ENST00000268053.11	NP_000772.2
LOC124903524	XR_007064709.1	n.1734C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.235G>A	p.Val79Ile	missense_variant	1/9	1	NM_000781.3	ENSP00000268053	P1
	ENST00000568496.2	n.1086C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00276 AC: 695 AN: 251480 Hom.: 2 AF XY: 0.00260 AC XY: 354 AN XY: 135916

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00476

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00517 AC: 7551 AN: 1461888 Hom.: 24 Cov.: 32 AF XY: 0.00488 AC XY: 3548 AN XY: 727248

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00626

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74464

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00464 Hom.: 2

Bravo AF: 0.00337

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00255 AC: 310

EpiCase AF: 0.00567

EpiControl AF: 0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.43
DANN	Benign	0.78
DEOGEN2	Benign	0.082	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.072
Sift	Benign	0.55	T;T
Sift4G	Benign	0.40	T;.
Polyphen		0.0	B;.
Vest4		0.081
MVP		0.58
MPC		0.27
ClinPred		0.0035	T
GERP RS		-5.2
Varity_R		0.13
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs143655263; hg19: chr15-74659692;