rs121912814

Variant names:

• chr15-74338761-A-C
• NM_000781.3:c.1244T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-74338761-A-C
• chr15-74338761-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000781.3(CYP11A1):​c.1244T>G​(p.Val415Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V415E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP11A1 NM_000781.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-74338761-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 17523.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.1244T>G	p.Val415Gly	missense_variant	Exon 8 of 9	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.770T>G	p.Val257Gly	missense_variant	Exon 8 of 9		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.1244T>G	p.Val415Gly	missense_variant	Exon 8 of 9	1	NM_000781.3	ENSP00000268053.6
CYP11A1	ENST00000358632.8	c.770T>G	p.Val257Gly	missense_variant	Exon 8 of 9	2		ENSP00000351455.4
CYP11A1	ENST00000435365.5	n.1165T>G		non_coding_transcript_exon_variant	Exon 7 of 8	3		ENSP00000391081.1
CYP11A1	ENST00000498141.1	n.87T>G		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1244T>G (p.V415G) alteration is located in exon 8 (coding exon 8) of the CYP11A1 gene. This alteration results from a T to G substitution at nucleotide position 1244, causing the valine (V) at amino acid position 415 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.69
MutPred		0.79		.;Loss of stability (P = 0.0377);
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-74631102;