15-51338638-G-A

Variant names:

• chr15-51338638-G-A
• rs6493497
• NM_000103.4:c.-182C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000103.4(CYP19A1):​c.-182C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 152,192 control chromosomes in the GnomAD database, including 2,353 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2353 hom., cov: 32)
  • Exomes 𝑓: 0.038 (0 hom.)
• Consequence: CYP19A1 NM_000103.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 38 publications found

Genes affected

CYP19A1 (HGNC:2594): (cytochrome P450 family 19 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 and catalyzes the last steps of estrogen biosynthesis. Mutations in this gene can result in either increased or decreased aromatase activity; the associated phenotypes suggest that estrogen functions both as a sex steroid hormone and in growth or differentiation. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]

CYP19A1 Gene-Disease associations (from GenCC):

• aromatase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• aromatase excess syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000103.4. 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
	CYP19A1	NM_000103.4	MANE Select	c.-182C>T		upstream_gene	N/A	NP_000094.2
	CYP19A1	NM_031226.3		c.-291C>T		upstream_gene	N/A	NP_112503.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.-182C>T		upstream_gene	N/A	ENSP00000379683.1
	CYP19A1	ENST00000439712.6	TSL:1	n.-426C>T		upstream_gene	N/A	ENSP00000390614.2
	CYP19A1	ENST00000557934.5	TSL:1	n.-182C>T		upstream_gene	N/A	ENSP00000454004.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24934 AN: 152046 Hom.: 2340 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.0637

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.0385 AC: 1 AN: 26 Hom.: 0 Cov.: 0 AF XY: 0.0556 AC XY: 1 AN XY: 18

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0556 AC: 1 AN: 18

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.164 AC: 24996 AN: 152166 Hom.: 2353 Cov.: 32 AF XY: 0.165 AC XY: 12275 AN XY: 74396

African (AFR) AF: 0.257 AC: 10655 AN: 41486

American (AMR) AF: 0.157 AC: 2401 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1068 AN: 5180

South Asian (SAS) AF: 0.259 AC: 1249 AN: 4818

European-Finnish (FIN) AF: 0.0637 AC: 676 AN: 10606

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7957 AN: 67992

Other (OTH) AF: 0.170 AC: 359 AN: 2108

Alfa AF: 0.146 Hom.: 3173

Bravo AF: 0.175

Asia WGS AF: 0.284 AC: 987 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.50
PhyloP100		0.36
PromoterAI		-0.061	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6493497; hg19: chr15-51630835;