rs700519

Positions:

chr15-51215771-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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 Likely benign.

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP19A1	NM_000103.4 linkuse as main transcript	c.790C>T	p.Arg264Cys	missense_variant	7/10	ENST00000396402.6	NP_000094.2
MIR4713HG	NR_146310.1 linkuse as main transcript	n.195-62212G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6 linkuse as main transcript	c.790C>T	p.Arg264Cys	missense_variant	7/10	1	NM_000103.4	ENSP00000379683	P1	P11511-1
MIR4713HG	ENST00000559909.1 linkuse as main transcript	n.195-62212G>A		intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes

AF:

0.0761

AC:

19115

AN:

251272

Hom.:

1433

AF XY:

0.0792

AC XY:

10760

AN XY:

135800

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 SAS exome

AF:

0.215

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

Gnomad4 AFR exome

AF:

0.170

Gnomad4 AMR exome

AF:

0.0565

Gnomad4 ASJ exome

AF:

0.0353

Gnomad4 EAS exome

AF:

0.215

Gnomad4 SAS exome

AF:

0.203

Gnomad4 FIN exome

AF:

0.0413

Gnomad4 NFE exome

AF:

0.0312

Gnomad4 OTH exome

AF:

0.0565

GnomAD4 genome

AF:

0.0807

AC:

12276

AN:

152136

Hom.:

861

Cov.:

AF XY:

0.0834

AC XY:

6205

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.162

Gnomad4 AMR

AF:

0.0422

Gnomad4 ASJ

AF:

0.0418

Gnomad4 EAS

AF:

0.170

Gnomad4 SAS

AF:

0.208

Gnomad4 FIN

AF:

0.0456

Gnomad4 NFE

AF:

0.0333

Gnomad4 OTH

AF:

0.0516

Alfa

AF:

0.0446

Hom.:

517

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aromatase deficiency

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;D;D;.;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.76

.;.;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L;.;.

MutationTaster

Benign

0.36

P;P;P;P

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.6

D;D;D;D;D

REVEL

Benign

0.12

Sift

Benign

0.044

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;.

Polyphen

0.011

B;B;B;.;.

Vest4

0.083

MPC

0.17

ClinPred

0.025

GERP RS

4.4

Varity_R

0.10

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over