rs3751592

Positions:

• chr15-51314381-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000103.4(CYP19A1):​c.-39+24114A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,680 control chromosomes in the GnomAD database, including 7,208 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 (7208 hom., cov: 31)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.-39+24114A>G		intron_variant		ENST00000396402.6	NP_000094.2
CYP19A1	NM_001347248.1	c.-39+9435A>G		intron_variant			NP_001334177.1
CYP19A1	NM_001347249.2	c.-39+4052A>G		intron_variant			NP_001334178.1
CYP19A1	NM_031226.3	c.-39+9435A>G		intron_variant			NP_112503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.-39+24114A>G		intron_variant		1	NM_000103.4	ENSP00000379683	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46283 AN: 151562 Hom.: 7205 Cov.: 31

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.305 AC: 46305 AN: 151680 Hom.: 7208 Cov.: 31 AF XY: 0.303 AC XY: 22438 AN XY: 74132

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.261

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.318

Alfa AF: 0.320 Hom.: 10767

Bravo AF: 0.316

Asia WGS AF: 0.167 AC: 581 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.42
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs3751592; hg19: chr15-51606578;