NM_000103.4:c.-39+12984A>G

Variant names:

• chr15-51325511-T-C
• rs2445762
• NM_000103.4:c.-39+12984A>G

Variant summary

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

The NM_000103.4(CYP19A1):​c.-39+12984A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 151,942 control chromosomes in the GnomAD database, including 7,598 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 0.31 (7598 hom., cov: 32)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.379
• Publications: 40 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=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.-39+12984A>G		intron_variant	Intron 1 of 9	ENST00000396402.6	NP_000094.2
CYP19A1	NM_031226.3	c.-147-1587A>G		intron_variant	Intron 1 of 10		NP_112503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.-39+12984A>G		intron_variant	Intron 1 of 9	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47126 AN: 151824 Hom.: 7598 Cov.: 32

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.305

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.310 AC: 47164 AN: 151942 Hom.: 7598 Cov.: 32 AF XY: 0.308 AC XY: 22839 AN XY: 74228

African (AFR) AF: 0.381 AC: 15778 AN: 41394

American (AMR) AF: 0.371 AC: 5667 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 920 AN: 3468

East Asian (EAS) AF: 0.306 AC: 1575 AN: 5154

South Asian (SAS) AF: 0.235 AC: 1128 AN: 4808

European-Finnish (FIN) AF: 0.219 AC: 2309 AN: 10544

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18859 AN: 67978

Other (OTH) AF: 0.305 AC: 645 AN: 2112

Alfa AF: 0.288 Hom.: 21812

Bravo AF: 0.329

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.1
DANN	Benign	0.40
PhyloP100		-0.38
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: rs2445762; hg19: chr15-51617708;