rs727479

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

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 cumulative frequency of 0.679 (AC=183,949) in the gnomAD database across 270,982 control chromosomes, including 62,811 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.777. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars).

Frequency

Genomes: 𝑓 0.69 ( 36079 hom., cov: 28)

Exomes 𝑓: 0.67 ( 26732 hom. )

Consequence

CYP19A1
NM_000103.4 intron

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -3.08

Publications

84 publications found

Variant links:

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: Natera, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
aromatase excess syndrome
Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

CYP19A1 links:

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

MIR4713HG links:

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]

MIR4713 links:

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: Benign. The variant received -12 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7768 — exceeds 5%% threshold (BA1 applied)

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.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	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

Gene	Transcript	Tags	HGVSc	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.:

show subpopulations

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

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1264

2528

3791

5055

6319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

334

668

1002

1336

1670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.688

AC:

104207

AN:

151562

Hom.:

36079

Cov.:

AF XY:

0.688

AC XY:

50955

AN XY:

74048

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1620

3240

4859

6479

8099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.670

Hom.:

34227

Bravo

AF:

0.686

Asia WGS

AF:

0.693

AC:

2411

AN:

3478

Local populations

Turkish Variome

AF:

0.594

AC:

917

AN:

1544

Hom.:

289

ABraOM SABE-WGS-1171

AF:

0.640

AC:

1499

AN:

2342

Hom.:

478

ClinVar

ClinVar submissions

Significance:drug response

Revision:no assertion criteria provided

View on ClinVar

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

(source)

DANN

Benign

0.37

PhyloP100

-3.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over