dbSNP rs104894138: CYP17A1:p.Arg96Trp (chr10-102837076-G-A) – ACMG Classification: Pathogenic (21 pts)

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3PM2PM5PP2PP3_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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000321538: Published functional studies demonstrate a damaging effect resulting in almost complete loss of enzyme activity (Laflamme et al., 1996" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96Q) has been classified 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.98

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
46,XY disorder of sex development due to isolated 17,20-lyase deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP17A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 21 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000321538: Published functional studies demonstrate a damaging effect resulting in almost complete loss of enzyme activity (Laflamme et al., 1996; Sahakitrungruang et al., 2009); SCV001415980: Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 8550762, 10720067).; SCV003800630: 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).

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-102837075-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2356 (below the threshold of 3.09). Trascript score misZ: 1.3377 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, 46,XY disorder of sex development due to isolated 17,20-lyase deficiency.

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/Likely_pathogenic. ClinVar VariationId is 1785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000102.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP17A1	NM_000102.4	MANE Select	c.286C>T	p.Arg96Trp	missense	Exon 1 of 8	NP_000093.1	Q1HB44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP17A1	ENST00000369887.4	TSL:1 MANE Select	c.286C>T	p.Arg96Trp	missense	Exon 1 of 8	ENSP00000358903.3	P05093
CYP17A1	ENST00000960108.1		c.286C>T	p.Arg96Trp	missense	Exon 1 of 8	ENSP00000630166.1
CYP17A1	ENST00000960123.1		c.286C>T	p.Arg96Trp	missense	Exon 1 of 8	ENSP00000630182.1

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

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

251326

AF XY:

0.0000368

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 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

African (AFR)

AF:

0.0000604

AC:

AN:

33122

American (AMR)

AF:

0.0000447

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39622

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5260

European-Non Finnish (NFE)

AF:

0.0000720

AC:

AN:

1096916

Other (OTH)

AF:

0.0000669

AC:

AN:

59758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000454

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

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of steroid 17-alpha-monooxygenase (5)

not provided (2)

17-alpha-hydroxylase/17,20-lyase deficiency, combined complete (1)

Congenital adrenal hyperplasia (1)

Differences in sex development (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

4.3

PhyloP100

2.0

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MVP

0.96

MPC

0.98

ClinPred

0.99

GERP RS

3.5

PromoterAI

-0.039

Neutral

(source)

Varity_R

0.97

gMVP

0.92

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over