ENST00000369887:c.*165dupT

Variant names:

• chr10-102830536-G-GA
• rs45455494
• NM_000102.4:c.*165dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000369887.4(CYP17A1):​c.*165dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 357,468 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.21 (0 hom.)
• Consequence: CYP17A1 ENST00000369887.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0520
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00513 (749/145884) while in subpopulation AFR AF = 0.0153 (614/40010). AF 95% confidence interval is 0.0143. There are 2 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000369887.4. 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.*165dupT		3_prime_UTR	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.*165dupT		3_prime_UTR	Exon 8 of 8	ENSP00000358903.3	P05093
	CYP17A1	ENST00000960119.1		c.*165dupT		splice_region	Exon 8 of 8	ENSP00000630178.1
	CYP17A1	ENST00000960121.1		c.*165dupT		splice_region	Exon 8 of 8	ENSP00000630180.1

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 743 AN: 145816 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00246

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.00179

Gnomad SAS AF: 0.00260

Gnomad FIN AF: 0.00277

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.000606

Gnomad OTH AF: 0.00500

GnomAD4 exome AF: 0.213 AC: 45081 AN: 211584 Hom.: 0 Cov.: 3 AF XY: 0.212 AC XY: 23746 AN XY: 111948

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

African (AFR) AF: 0.225 AC: 1310 AN: 5826

American (AMR) AF: 0.224 AC: 1939 AN: 8670

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 1434 AN: 6700

East Asian (EAS) AF: 0.212 AC: 3118 AN: 14694

South Asian (SAS) AF: 0.221 AC: 4351 AN: 19674

European-Finnish (FIN) AF: 0.189 AC: 2812 AN: 14894

Middle Eastern (MID) AF: 0.218 AC: 206 AN: 944

European-Non Finnish (NFE) AF: 0.213 AC: 27256 AN: 127766

Other (OTH) AF: 0.214 AC: 2655 AN: 12416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00513 AC: 749 AN: 145884 Hom.: 2 Cov.: 32 AF XY: 0.00486 AC XY: 344 AN XY: 70766

African (AFR) AF: 0.0153 AC: 614 AN: 40010

American (AMR) AF: 0.00246 AC: 36 AN: 14642

Ashkenazi Jewish (ASJ) AF: 0.000295 AC: 1 AN: 3390

East Asian (EAS) AF: 0.00179 AC: 9 AN: 5022

South Asian (SAS) AF: 0.00260 AC: 12 AN: 4610

European-Finnish (FIN) AF: 0.00277 AC: 25 AN: 9036

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.000606 AC: 40 AN: 65980

Other (OTH) AF: 0.00495 AC: 10 AN: 2022

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital adrenal hyperplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.052
Mutation Taster		=100/0	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: rs45455494; hg19: chr10-104590293;