rs104894155

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000102.4(CYP17A1):c.1247G>A(p.Arg416His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,569,960 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R416C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CYP17A1
NM_000102.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.32

Variant links:

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]

CYP17A1 links:

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]

WBP1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 3) in uniprot entity CP17A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000102.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-102830983-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2735478.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 10-102830982-C-T is Pathogenic according to our data. Variant chr10-102830982-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP17A1	NM_000102.4 linkuse as main transcript	c.1247G>A	p.Arg416His	missense_variant	8/8	ENST00000369887.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP17A1	ENST00000369887.4 linkuse as main transcript	c.1247G>A	p.Arg416His	missense_variant	8/8	1	NM_000102.4	P3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000169

AC:

AN:

1417742

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

701798

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000212

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of steroid 17-alpha-monooxygenase

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Missense variant c.1247G>A in Exon 8 of the CYP17A1 gene that results in the amino acid substitution p.Arg416His was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic (Variant ID-1804). This variant has been previously reported in Ergun-Longmire B et al., 2006. Expression studies revealed no detectable activity of the encoded protein (Ergun-Longmire B et al., 2006). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

CYP17A1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2022

The CYP17A1 c.1247G>A variant is predicted to result in the amino acid substitution p.Arg416His. This variant was reported in an individual with steroid-17 alpha-hydroxylase deficiency (Ergun-Longmire et al. 2006. PubMed ID: 16849412; Rosa et al. 2006. PubMed ID: 17192295; Alswailem et al. 2017. PubMed ID: 28870780; Alswailem et al. 2020. PubMed ID: 32784047). This variant is reported in 0.0011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-104590739-C-T). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 416 of the CYP17A1 protein (p.Arg416His). This variant is present in population databases (rs104894155, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of CYP17A1-related conditions (PMID: 16849412, 17192295, 28870780, 32784047). ClinVar contains an entry for this variant (Variation ID: 1804). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 17192295). This variant disrupts the p.Arg416 amino acid residue in CYP17A1. Other variant(s) that disrupt this residue have been observed in individuals with CYP17A1-related conditions (PMID: 11422109, 16772352), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

17-alpha-hydroxylase/17,20-lyase deficiency, combined complete

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

Polyphen

1.0

.;.;D;.;.

Vest4

0.98

MutPred

0.98

.;.;Gain of catalytic residue at L418 (P = 0.043);.;.;

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

4.5

Varity_R

0.89

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over