rs700519

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000103.4(CYP19A1):c.790C>T(p.Arg264Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,613,786 control chromosomes in the GnomAD database, including 5,264 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.081 ( 861 hom., cov: 33)

Exomes 𝑓: 0.052 ( 4403 hom. )

Consequence

CYP19A1
NM_000103.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.17

Publications

149 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016607046).

BP6

Variant 15-51215771-G-A is Benign according to our data. Variant chr15-51215771-G-A is described in ClinVar as Benign. ClinVar VariationId is 137064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.197 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP19A1	NM_000103.4	MANE Select	c.790C>T	p.Arg264Cys	missense	Exon 7 of 10	NP_000094.2
CYP19A1	NM_001347248.1		c.790C>T	p.Arg264Cys	missense	Exon 7 of 10	NP_001334177.1
CYP19A1	NM_001347249.2		c.790C>T	p.Arg264Cys	missense	Exon 7 of 10	NP_001334178.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.790C>T	p.Arg264Cys	missense	Exon 7 of 10	ENSP00000379683.1
CYP19A1	ENST00000559878.5	TSL:1	c.790C>T	p.Arg264Cys	missense	Exon 6 of 9	ENSP00000453149.1
CYP19A1	ENST00000439712.6	TSL:1	n.790C>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000390614.2

Frequencies

GnomAD3 genomes

AF:

0.0807

AC:

12262

AN:

152018

Hom.:

860

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0424

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.0456

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0333

Gnomad OTH

AF:

0.0478

GnomAD2 exomes

AF:

0.0761

AC:

19115

AN:

251272

AF XY:

0.0792

show subpopulations

Gnomad AFR exome

AF:

0.165

Gnomad AMR exome

AF:

0.0589

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.137

Gnomad FIN exome

AF:

0.0443

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0487

GnomAD4 exome

AF:

0.0518

AC:

75646

AN:

1461650

Hom.:

4403

Cov.:

AF XY:

0.0557

AC XY:

40531

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.170

AC:

5702

AN:

33468

American (AMR)

AF:

0.0565

AC:

2526

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0353

AC:

921

AN:

26124

East Asian (EAS)

AF:

0.215

AC:

8528

AN:

39662

South Asian (SAS)

AF:

0.203

AC:

17478

AN:

86254

European-Finnish (FIN)

AF:

0.0413

AC:

2203

AN:

53354

Middle Eastern (MID)

AF:

0.0361

AC:

208

AN:

5764

European-Non Finnish (NFE)

AF:

0.0312

AC:

34666

AN:

1111924

Other (OTH)

AF:

0.0565

AC:

3414

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4930

9861

14791

19722

24652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1596

3192

4788

6384

7980

<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:

0.0807

AC:

12276

AN:

152136

Hom.:

861

Cov.:

AF XY:

0.0834

AC XY:

6205

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.162

AC:

6713

AN:

41480

American (AMR)

AF:

0.0422

AC:

645

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0418

AC:

145

AN:

3472

East Asian (EAS)

AF:

0.170

AC:

879

AN:

5174

South Asian (SAS)

AF:

0.208

AC:

1002

AN:

4818

European-Finnish (FIN)

AF:

0.0456

AC:

483

AN:

10592

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0333

AC:

2263

AN:

67986

Other (OTH)

AF:

0.0516

AC:

109

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

554

1108

1662

2216

2770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0504

Hom.:

1449

Bravo

AF:

0.0800

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.164

AC:

721

ESP6500EA

AF:

0.0330

AC:

283

ExAC

AF:

0.0796

AC:

9662

Asia WGS

AF:

0.200

AC:

694

AN:

3476

EpiCase

AF:

0.0328

EpiControl

AF:

0.0286

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aromatase deficiency (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

2.2

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.12

Sift

Benign

0.044

Sift4G

Uncertain

0.0040

Polyphen

0.011

Vest4

0.083

MPC

0.17

ClinPred

0.025

GERP RS

4.4

Varity_R

0.10

gMVP

0.39

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over