10-102831589-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000102.4(CYP17A1):c.1162A>G(p.Lys388Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CYP17A1 NM_000102.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

Genes affected

CYP17A1 (HGNC:2593): (cytochrome P450 family 17 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 endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. Mutations in this gene are associated with isolated steroid-17 alpha-hydroxylase deficiency, 17-alpha-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia. [provided by RefSeq, Jul 2008]

WBP1L (HGNC:23510): (WW domain binding protein 1 like) Predicted to enable ubiquitin protein ligase binding activity. Predicted to act upstream of or within CXCL12-activated CXCR4 signaling pathway; hemopoiesis; and positive regulation of protein ubiquitination. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP17A1	NM_000102.4	c.1162A>G	p.Lys388Glu	missense_variant	7/8	ENST00000369887.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP17A1	ENST00000369887.4	c.1162A>G	p.Lys388Glu	missense_variant	7/8	1	NM_000102.4	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.1162A>G (p.K388E) alteration is located in exon 7 (coding exon 7) of the CYP17A1 gene. This alteration results from a A to G substitution at nucleotide position 1162, causing the lysine (K) at amino acid position 388 to be replaced by a glutamic acid (E). 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	Benign	0.18
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.49	T
Polyphen		0.93	.;.;P;.;.
Vest4		0.38
MutPred		0.74		.;.;Loss of methylation at K388 (P = 0.0047);.;.;
MVP		0.88
MPC		0.54
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.68
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060499582; hg19: chr10-104591346;