Genetic Variant CYP19A1:p.Arg264Leu (chr15-51215770-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000103.4(CYP19A1):c.791G>T(p.Arg264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264C) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYP19A1
NM_000103.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.666

Publications

6 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07944238).

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.791G>T	p.Arg264Leu	missense	Exon 7 of 10	NP_000094.2
CYP19A1	NM_001347248.1		c.791G>T	p.Arg264Leu	missense	Exon 7 of 10	NP_001334177.1
CYP19A1	NM_001347249.2		c.791G>T	p.Arg264Leu	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.791G>T	p.Arg264Leu	missense	Exon 7 of 10	ENSP00000379683.1
CYP19A1	ENST00000559878.5	TSL:1	c.791G>T	p.Arg264Leu	missense	Exon 6 of 9	ENSP00000453149.1
CYP19A1	ENST00000439712.6	TSL:1	n.791G>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000390614.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251296

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111934

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.71

M_CAP

Benign

0.032

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

PhyloP100

0.67

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.13

Sift

Benign

0.28

Sift4G

Benign

0.079

Polyphen

0.0

Vest4

0.16

MutPred

0.30

Loss of disorder (P = 0.0324)

MVP

0.47

MPC

0.15

ClinPred

0.067

GERP RS

-1.5

Varity_R

0.11

gMVP

0.41

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over