rs104894135

Positions:

• chr10-102835374-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000102.4(CYP17A1):​c.316T>C​(p.Ser106Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP17A1 NM_000102.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.66

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]

ACMG classification

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, 0.987
• PP5: Variant 10-102835374-A-G is Pathogenic according to our data. Variant chr10-102835374-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP17A1	NM_000102.4	c.316T>C	p.Ser106Pro	missense_variant	2/8	ENST00000369887.4	NP_000093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP17A1	ENST00000369887.4	c.316T>C	p.Ser106Pro	missense_variant	2/8	1	NM_000102.4	ENSP00000358903	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726824

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 17-alpha-monooxygenase Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2019	Published functional studies demonstrate a decreased 17 alpha hydroxylase activity in comparison to wildtype (Lin et al., 1991); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7811386, 14560315, 1714904, 1621662, 25697092, 27096365, 29278670, 16477341) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 1714904). 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 not expected to disrupt CYP17A1 protein function. ClinVar contains an entry for this variant (Variation ID: 1780). This missense change has been observed in individual(s) with 17-alpha-hydroxylase deficiency (PMID: 1714904, 16477341). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs104894135, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 106 of the CYP17A1 protein (p.Ser106Pro). -

CYP17A1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

The CYP17A1 c.316T>C variant is predicted to result in the amino acid substitution p.Ser106Pro. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with 17-alpha-hydroxylase/17,20 lyase deficiency (Lin et al. 1991. PubMed ID: 1714904; Wong et al. 2006. PubMed ID: 16477341; Zhang et al. 2015. PubMed ID: 25697092; Sun et al. 2017. PubMed ID: 29278670). In vitro experimental studies have demonstrated that the p.Ser106Pro variant results in a complete loss of catalytic activity when co-incubated with several different steroid substrates (Lin et al. 1991. PubMed ID: 1714904). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

17-alpha-hydroxylase/17,20-lyase deficiency, combined complete Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.4	.;.;M;.
MutationTaster	Benign	0.99	A
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.4	.;.;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	.;.;D;.
Sift4G	Uncertain	0.0050	.;.;D;.
Polyphen		1.0	.;.;D;.
Vest4		0.95
MutPred		0.92		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.93
MPC		1.1
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.80

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

Other links and lift over

dbSNP: rs104894135; hg19: chr10-104595131;