10-102830737-C-T

Variant names:

• chr10-102830737-C-T
• rs771259164
• NM_000102.4:c.1492G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000102.4(CYP17A1):​c.1492G>A​(p.Ala498Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A498V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CYP17A1 NM_000102.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 1 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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000102.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3012902).

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.1492G>A	p.Ala498Thr	missense	Exon 8 of 8	NP_000093.1	Q1HB44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP17A1	ENST00000369887.4	TSL:1 MANE Select	c.1492G>A	p.Ala498Thr	missense	Exon 8 of 8	ENSP00000358903.3	P05093
	CYP17A1	ENST00000960108.1		c.1519G>A	p.Ala507Thr	missense	Exon 8 of 8	ENSP00000630166.1
	CYP17A1	ENST00000960123.1		c.1519G>A	p.Ala507Thr	missense	Exon 8 of 8	ENSP00000630182.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 241958 AF XY: 0.00000764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

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: 6.89e-7 AC: 1 AN: 1451588 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722086

African (AFR) AF: 0.00 AC: 0 AN: 33288

American (AMR) AF: 0.0000226 AC: 1 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104636

Other (OTH) AF: 0.00 AC: 0 AN: 59984

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.021	D
Polyphen		0.97	D
Vest4		0.41
MutPred		0.41		Loss of catalytic residue at A498 (P = 0.0276)
MVP		0.84
MPC		0.73
ClinPred		0.66	D
GERP RS		5.6
Varity_R		0.26
gMVP		0.50
Mutation Taster		=62/38	polymorphism

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: rs771259164; hg19: chr10-104590494;