10-102830742-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM2PM5PP3_StrongPP5_Very_Strong

The NM_000102.4(CYP17A1):c.1487G>A(p.Arg496His) variant causes a missense change. The variant allele was found at a frequency of 0.00000374 in 1,602,300 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R496C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CYP17A1
NM_000102.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 4.09

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.

PS1

Transcript NM_000102.4 (CYP17A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-102830743-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1524567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 10-102830742-C-T is Pathogenic according to our data. Variant chr10-102830742-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2681111.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.1487G>A	p.Arg496His	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.1487G>A	p.Arg496His	missense_variant	8/8	1	NM_000102.4	P3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000828

AC:

AN:

241520

Hom.:

AF XY:

0.00000765

AC XY:

AN XY:

130670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000555

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1450564

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721620

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151736

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74084

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 09, 2023

This variant disrupts the p.Arg496 amino acid residue in CYP17A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1515452, 9888582). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 10720067). 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. This missense change has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 10720067, 33780934). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 496 of the CYP17A1 protein (p.Arg496His). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Deficiency of steroid 17-alpha-monooxygenase

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

Polyphen

1.0

.;.;D;.;.

Vest4

0.83

MutPred

0.93

.;.;Loss of MoRF binding (P = 0.0082);.;.;

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

5.6

Varity_R

0.82

gMVP

0.93

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

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