chr15-74343030-A-G

Variant names:

• chr15-74343030-A-G
• rs1060499732
• NM_000781.3:c.937T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000781.3(CYP11A1):​c.937T>C​(p.Phe313Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F313F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP11A1 NM_000781.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09292513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.937T>C	p.Phe313Leu	missense_variant	Exon 5 of 9	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.463T>C	p.Phe155Leu	missense_variant	Exon 5 of 9		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.937T>C	p.Phe313Leu	missense_variant	Exon 5 of 9	1	NM_000781.3	ENSP00000268053.6
CYP11A1	ENST00000358632.8	c.463T>C	p.Phe155Leu	missense_variant	Exon 5 of 9	2		ENSP00000351455.4
CYP11A1	ENST00000566674.5	c.463T>C	p.Phe155Leu	missense_variant	Exon 5 of 6	5		ENSP00000456941.1
CYP11A1	ENST00000435365.5	n.937T>C		non_coding_transcript_exon_variant	Exon 5 of 8	3		ENSP00000391081.1

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

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

Mar 29, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.34
DEOGEN2	Benign	0.050	.;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	.;N;.
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.095
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.81	T;T;.
Polyphen		0.0010	.;B;.
Vest4		0.028
MutPred		0.42		.;Gain of ubiquitination at K310 (P = 0.0804);.;
MVP		0.70
MPC		0.38
ClinPred		0.060	T
GERP RS		2.1
Varity_R		0.24
gMVP		0.35

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: rs1060499732; hg19: chr15-74635371;