NM_000103.4:c.452-2378A>G

Variant names:

• chr15-51224903-T-C
• rs12595627
• NM_000103.4:c.452-2378A>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.452-2378A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 152,014 control chromosomes in the GnomAD database, including 32,878 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 0.66 (32878 hom., cov: 31)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 9 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]

MIR4713HG (HGNC:53124): (MIR4713 host gene)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.726 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	NM_000103.4	MANE Select	c.452-2378A>G		intron	N/A	NP_000094.2
	CYP19A1	NM_001347248.1		c.452-2378A>G		intron	N/A	NP_001334177.1	P11511-1
	CYP19A1	NM_001347249.2		c.452-2378A>G		intron	N/A	NP_001334178.1	P11511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.452-2378A>G		intron	N/A	ENSP00000379683.1	P11511-1
	CYP19A1	ENST00000559878.5	TSL:1	c.452-2378A>G		intron	N/A	ENSP00000453149.1	P11511-1
	CYP19A1	ENST00000405913.7	TSL:1	c.452-2378A>G		intron	N/A	ENSP00000383930.3	P11511-2

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99891 AN: 151896 Hom.: 32838 Cov.: 31

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.624

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

GnomAD4 genome AF: 0.658 AC: 99983 AN: 152014 Hom.: 32878 Cov.: 31 AF XY: 0.660 AC XY: 49049 AN XY: 74320

African (AFR) AF: 0.676 AC: 28026 AN: 41442

American (AMR) AF: 0.611 AC: 9330 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2345 AN: 3468

East Asian (EAS) AF: 0.690 AC: 3568 AN: 5172

South Asian (SAS) AF: 0.746 AC: 3599 AN: 4822

European-Finnish (FIN) AF: 0.659 AC: 6980 AN: 10586

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44082 AN: 67942

Other (OTH) AF: 0.625 AC: 1313 AN: 2102

Alfa AF: 0.657 Hom.: 5539

Bravo AF: 0.652

Asia WGS AF: 0.686 AC: 2386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	5.9
DANN	Benign	0.28
PhyloP100		0.24
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: rs12595627; hg19: chr15-51517100;