rs104894138

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000102.4(CYP17A1):c.286C>T(p.Arg96Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,596,880 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

CYP17A1
NM_000102.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.98

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 10-102837076-G-A is Pathogenic according to our data. Variant chr10-102837076-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102837076-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP17A1	NM_000102.4 link	c.286C>T	p.Arg96Trp	missense_variant	1/8	ENST00000369887.4	NP_000093.1	P05093Q1HB44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP17A1	ENST00000369887.4 link	c.286C>T	p.Arg96Trp	missense_variant	1/8	1	NM_000102.4	ENSP00000358903.3		P05093

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251326

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1444710

Hom.:

Cov.:

AF XY:

0.0000695

AC XY:

AN XY:

719794

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000720

Gnomad4 OTH exome

AF:

0.0000669

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000236

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of steroid 17-alpha-monooxygenase

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 96 of the CYP17A1 protein (p.Arg96Trp). This variant is present in population databases (rs104894138, gnomAD 0.006%). This missense change has been observed in individuals with congenital adrenal hyperplasia (PMID: 8550762, 21340163, 28008861). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1785). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP17A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 8550762, 10720067). This variant disrupts the p.Arg96 amino acid residue in CYP17A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16569739, 21846181, 23291414, 23466679, 26543560, 28008861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	Published functional studies demonstrate a damaging effect resulting in almost complete loss of enzyme activity (Laflamme et al., 1996; Sahakitrungruang et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14671162, 12573489, 19470621, 21340163, 8550762, 31589614, 25697092, 30229581, 29255217, 27271787, 33547012, 29144824, 24485502, 31034465, Mohnach[CaseReport]2018) -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

Congenital adrenal hyperplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 30, 2023

Variant summary: CYP17A1 c.286C>T (p.Arg96Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251326 control chromosomes (gnomAD). c.286C>T has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia/17 alpha-hydroxylase/17,20-lyase deficiency (e.g. Laflamme_1996, Biason-Lauber_2000, Costenaro_2010). These data indicate that the variant is very likely to be associated with disease. Experimental studies examining the effect of the variant on protein function have shown that it results in an enzyme activity of approximately 10%-30% of the normal WT protein (e.g. Laflamme_1996, Biason-Lauber_2000). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;.;D;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

4.3

.;.;H;.;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.0

.;.;D;.;.

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;.;D;.;.

Sift4G

Pathogenic

0.0

.;.;D;.;.

Polyphen

1.0

.;.;D;.;.

Vest4

0.95

MVP

0.96

MPC

0.98

ClinPred

0.99

GERP RS

3.5

Varity_R

0.97

gMVP

0.92

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

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