Genetic Variant CYP19A1:c.*595C>G (chr15-51221725-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000405913.7(CYP19A1):c.*595C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 152,640 control chromosomes in the GnomAD database, including 14,929 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 0.43 ( 14843 hom., cov: 33)

Exomes 𝑓: 0.49 ( 86 hom. )

Consequence

CYP19A1
ENST00000405913.7 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.331

Publications

7 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 links:

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

MIR4713HG links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4 link	c.628+624C>G		intron_variant	Intron 5 of 9	ENST00000396402.6	NP_000094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6 link	c.628+624C>G		intron_variant	Intron 5 of 9	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes

AF:

0.426

AC:

64705

AN:

151916

Hom.:

14845

Cov.:

show subpopulations

Gnomad AFR

AF:

0.245

Gnomad AMI

AF:

0.524

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.554

Gnomad EAS

AF:

0.498

Gnomad SAS

AF:

0.390

Gnomad FIN

AF:

0.493

Gnomad MID

AF:

0.436

Gnomad NFE

AF:

0.526

Gnomad OTH

AF:

0.449

GnomAD4 exome

AF:

0.490

AC:

297

AN:

606

Hom.:

Cov.:

AF XY:

0.478

AC XY:

152

AN XY:

318

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.352

AC:

AN:

108

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.300

AC:

AN:

South Asian (SAS)

AF:

0.318

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.537

AC:

233

AN:

434

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.426

AC:

64721

AN:

152034

Hom.:

14843

Cov.:

AF XY:

0.422

AC XY:

31400

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.245

AC:

10144

AN:

41464

American (AMR)

AF:

0.371

AC:

5676

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

1923

AN:

3468

East Asian (EAS)

AF:

0.497

AC:

2574

AN:

5176

South Asian (SAS)

AF:

0.392

AC:

1890

AN:

4822

European-Finnish (FIN)

AF:

0.493

AC:

5201

AN:

10550

Middle Eastern (MID)

AF:

0.438

AC:

128

AN:

292

European-Non Finnish (NFE)

AF:

0.526

AC:

35765

AN:

67958

Other (OTH)

AF:

0.447

AC:

943

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1836

3672

5507

7343

9179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.479

Hom.:

2219

Bravo

AF:

0.411

Asia WGS

AF:

0.384

AC:

1334

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.1

(source)

DANN

Benign

0.36

PhyloP100

0.33

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over