15-51242350-C-T
Variant names:
Variant summary
Our verdict is Likely benign. The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_Strong
The NM_000103.4(CYP19A1):c.145+418G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000167 (AC=2) in the gnomAD database across 119,758 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 28)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
CYP19A1
NM_000103.4 intron
NM_000103.4 intron
Scores
3
Clinical Significance
Not reported in ClinVar
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]
CYP19A1 Gene-Disease associations (from GenCC):
- aromatase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Natera, Ambry Genetics, Orphanet
- aromatase excess syndromeInheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
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]
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_000103.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Classification was made for transcript
Our verdict: Likely_benign. The variant received -3 points.
PM2
Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
BP4
Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_000103.4. You can select a different transcript below to see updated classification assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYP19A1 | TSL:1 MANE Select | c.145+418G>A | intron | N/A | ENSP00000379683.1 | P11511-1 | |||
| CYP19A1 | TSL:1 | c.145+418G>A | intron | N/A | ENSP00000453149.1 | P11511-1 | |||
| CYP19A1 | TSL:1 | c.145+418G>A | intron | N/A | ENSP00000383930.3 | P11511-2 |
Frequencies
GnomAD3 genomes 0.00000660 AC: 1AN: 151546Hom.: 0 Cov.: 28 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151546
Hom.:
Cov.:
28
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0000167 AC: 2AN: 119758Hom.: 0 AF XY: 0.0000159 AC XY: 1AN XY: 62972 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
119758
Hom.:
AF XY:
AC XY:
1
AN XY:
62972
show subpopulations
African (AFR)
AF:
AC:
0
AN:
2832
American (AMR)
AF:
AC:
0
AN:
4438
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
2968
East Asian (EAS)
AF:
AC:
0
AN:
4974
South Asian (SAS)
AF:
AC:
0
AN:
18052
European-Finnish (FIN)
AF:
AC:
0
AN:
6064
Middle Eastern (MID)
AF:
AC:
0
AN:
1542
European-Non Finnish (NFE)
AF:
AC:
2
AN:
72636
Other (OTH)
AF:
AC:
0
AN:
6252
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000660 AC: 1AN: 151546Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 73974 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
151546
Hom.:
Cov.:
28
AF XY:
AC XY:
0
AN XY:
73974
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41280
American (AMR)
AF:
AC:
0
AN:
15248
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3466
East Asian (EAS)
AF:
AC:
0
AN:
5044
South Asian (SAS)
AF:
AC:
0
AN:
4788
European-Finnish (FIN)
AF:
AC:
0
AN:
10540
Middle Eastern (MID)
AF:
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
AC:
1
AN:
67870
Other (OTH)
AF:
AC:
0
AN:
2090
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs727479 ;
hg19: chr15-51534547;