rs121434319

Variant names:

• chr10-102837199-TGAA-T
• rs121434319
• NM_000102.4:c.160_162delTTC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM4_Supporting PP5_Very_Strong

The NM_000102.4(CYP17A1):​c.160_162delTTC​(p.Phe54del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,455,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CYP17A1 NM_000102.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.25
• Publications: 2 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae)
• 46,XY disorder of sex development due to isolated 17,20-lyase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000102.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-102837199-TGAA-T is Pathogenic according to our data. Variant chr10-102837199-TGAA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP17A1	NM_000102.4	c.160_162delTTC	p.Phe54del	conservative_inframe_deletion	Exon 1 of 8	ENST00000369887.4	NP_000093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP17A1	ENST00000369887.4	c.160_162delTTC	p.Phe54del	conservative_inframe_deletion	Exon 1 of 8	1	NM_000102.4	ENSP00000358903.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251468 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1455960 Hom.: 0 AF XY: 0.0000207 AC XY: 15 AN XY: 724768

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39650

South Asian (SAS) AF: 0.000221 AC: 19 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106598

Other (OTH) AF: 0.00 AC: 0 AN: 60210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000968469), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 17-alpha-monooxygenase Pathogenic:3

Mar 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.160_162del, results in the deletion of 1 amino acid(s) of the CYP17A1 protein (p.Phe54del), but otherwise preserves the integrity of the reading frame. . This variant has been observed in individual(s) with 17 alpha-hydroxylase deficiency (Yanase T et al & Biason-Lauber A et al). This variant is also known as p.Phe53del in the literature. This variant has been reported to affect CYP17A1 protein function (Yanase T et al & Biason-Lauber A et al). This variant is reported with the allele frequency (0.002386%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. This p.Phe54del causes deletion of amino acid Phenylalanine at position 54. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:2

Feb 13, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CYP17A1 gene demonstrated a homozygous 3 base pair deletion in exon 1, c.160_162del. This sequence change results in an in-frame deletion of a single amino acid , phenylalanine, at position 54, p.Phe54del. This deletion has been previously described in three 46, XX phenotypic females with no sexual abnormalities and regular or irregular menstruation and one 46, XY phenotypic male with hypospadias and cryptorchidism (PMID: 8855840). Functional studies of the p.Phe54del in cell expression systems demonstrated a significant reduction in enzyme activity (PMID: 2808364). These collective evidences indicate that this sequence change is pathogenic. -

Oct 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.160_162del, results in the deletion of 1 amino acid(s) of the CYP17A1 protein (p.Phe54del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762179268, gnomAD 0.02%). This variant has been observed in individuals with 17 alpha-hydroxylase deficiency (PMID: 2808364, 10720067, 10877510, 19793597, 29068264). This variant is also known as p.Phe53del. ClinVar contains an entry for this variant (Variation ID: 1778). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CYP17A1 function (PMID: 2808364, 10720067). For these reasons, this variant has been classified as Pathogenic. -

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

Oct 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=75/25	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434319; hg19: chr10-104596956;