NM_000102.4:c.436+105A>C

Variant names:

• chr10-102835149-T-G
• rs743575
• NM_000102.4:c.436+105A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000102.4(CYP17A1):​c.436+105A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,155,236 control chromosomes in the GnomAD database, including 42,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4840 hom., cov: 31)
  • Exomes 𝑓: 0.27 (37836 hom.)
• Consequence: CYP17A1 NM_000102.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.415
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-102835149-T-G is Benign according to our data. Variant chr10-102835149-T-G is described in ClinVar as Benign. ClinVar VariationId is 761000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP17A1	NM_000102.4	MANE Select	c.436+105A>C		intron	N/A	NP_000093.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP17A1	ENST00000369887.4	TSL:1 MANE Select	c.436+105A>C		intron	N/A	ENSP00000358903.3
	CYP17A1	ENST00000639393.1	TSL:5	c.436+105A>C		intron	N/A	ENSP00000492651.1
	CYP17A1	ENST00000638971.1	TSL:5	c.436+105A>C		intron	N/A	ENSP00000492313.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37164 AN: 151246 Hom.: 4839 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.248

GnomAD4 exome AF: 0.267 AC: 267568 AN: 1003872 Hom.: 37836 Cov.: 14 AF XY: 0.262 AC XY: 135637 AN XY: 516718

African (AFR) AF: 0.160 AC: 3978 AN: 24848

American (AMR) AF: 0.191 AC: 8282 AN: 43400

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 6664 AN: 22762

East Asian (EAS) AF: 0.195 AC: 7298 AN: 37476

South Asian (SAS) AF: 0.130 AC: 9946 AN: 76652

European-Finnish (FIN) AF: 0.277 AC: 12025 AN: 43458

Middle Eastern (MID) AF: 0.286 AC: 1067 AN: 3734

European-Non Finnish (NFE) AF: 0.292 AC: 206208 AN: 706118

Other (OTH) AF: 0.266 AC: 12100 AN: 45424

GnomAD4 genome AF: 0.246 AC: 37170 AN: 151364 Hom.: 4840 Cov.: 31 AF XY: 0.242 AC XY: 17897 AN XY: 73896

African (AFR) AF: 0.166 AC: 6850 AN: 41258

American (AMR) AF: 0.233 AC: 3516 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1069 AN: 3466

East Asian (EAS) AF: 0.241 AC: 1239 AN: 5140

South Asian (SAS) AF: 0.127 AC: 610 AN: 4792

European-Finnish (FIN) AF: 0.267 AC: 2792 AN: 10464

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20330 AN: 67854

Other (OTH) AF: 0.247 AC: 517 AN: 2092

Alfa AF: 0.192 Hom.: 515

Bravo AF: 0.241

Asia WGS AF: 0.169 AC: 586 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Deficiency of steroid 17-alpha-monooxygenase Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.7
DANN	Benign	0.72
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs743575; hg19: chr10-104594906;