rs727479

Variant names:

• chr15-51242350-C-A
• rs727479
• NM_000103.4:c.145+418G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-51242350-C-A
• chr15-51242350-C-G
• chr15-51242350-C-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.145+418G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 270,982 control chromosomes in the GnomAD database, including 62,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.69 (36079 hom., cov: 28)
  • Exomes 𝑓: 0.67 (26732 hom.)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -3.08
• Publications: 84 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)

MIR4713 (HGNC:41899): (microRNA 4713) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 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.145+418G>T		intron	N/A	NP_000094.2
	CYP19A1	NM_001347248.1		c.145+418G>T		intron	N/A	NP_001334177.1	P11511-1
	CYP19A1	NM_001347249.2		c.145+418G>T		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.145+418G>T		intron	N/A	ENSP00000379683.1	P11511-1
	CYP19A1	ENST00000559878.5	TSL:1	c.145+418G>T		intron	N/A	ENSP00000453149.1	P11511-1
	CYP19A1	ENST00000405913.7	TSL:1	c.145+418G>T		intron	N/A	ENSP00000383930.3	P11511-2

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104107 AN: 151444 Hom.: 36036 Cov.: 28

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.640

GnomAD4 exome AF: 0.668 AC: 79742 AN: 119420 Hom.: 26732 AF XY: 0.675 AC XY: 42352 AN XY: 62766

African (AFR) AF: 0.789 AC: 2231 AN: 2826

American (AMR) AF: 0.605 AC: 2683 AN: 4432

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 1965 AN: 2962

East Asian (EAS) AF: 0.696 AC: 3447 AN: 4956

South Asian (SAS) AF: 0.738 AC: 13276 AN: 17998

European-Finnish (FIN) AF: 0.652 AC: 3940 AN: 6044

Middle Eastern (MID) AF: 0.584 AC: 901 AN: 1542

European-Non Finnish (NFE) AF: 0.652 AC: 47213 AN: 72434

Other (OTH) AF: 0.656 AC: 4086 AN: 6226

GnomAD4 genome AF: 0.688 AC: 104207 AN: 151562 Hom.: 36079 Cov.: 28 AF XY: 0.688 AC XY: 50955 AN XY: 74048

African (AFR) AF: 0.784 AC: 32438 AN: 41380

American (AMR) AF: 0.622 AC: 9490 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2342 AN: 3462

East Asian (EAS) AF: 0.687 AC: 3457 AN: 5030

South Asian (SAS) AF: 0.745 AC: 3566 AN: 4786

European-Finnish (FIN) AF: 0.659 AC: 6937 AN: 10528

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.647 AC: 43910 AN: 67818

Other (OTH) AF: 0.640 AC: 1348 AN: 2106

Alfa AF: 0.670 Hom.: 34227

Bravo AF: 0.686

Asia WGS AF: 0.693 AC: 2411 AN: 3478

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Letrozole response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.021
DANN	Benign	0.37
PhyloP100		-3.1
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: rs727479; hg19: chr15-51534547;