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rs700519

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 Uncertain significance.

Frequency

Genomes: 𝑓 0.081 ( 861 hom., cov: 33)
Exomes 𝑓: 0.052 ( 4403 hom. )

Consequence

CYP19A1
NM_000103.4 missense

Scores

5
12

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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

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 UniProt
CYP19A1NM_000103.4 linkuse as main transcriptc.790C>T p.Arg264Cys missense_variant 7/10 ENST00000396402.6
MIR4713HGNR_146310.1 linkuse as main transcriptn.195-62212G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP19A1ENST00000396402.6 linkuse as main transcriptc.790C>T p.Arg264Cys missense_variant 7/101 NM_000103.4 P1P11511-1
MIR4713HGENST00000559909.1 linkuse as main transcriptn.195-62212G>A intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0807
AC:
12262
AN:
152018
Hom.:
860
Cov.:
33
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.:
34
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.:
33
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:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Aromatase deficiency Benign:2
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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 specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 12, 2014This 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. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.33
Cadd
Benign
22
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
D
MetaRNN
Benign
0.0017
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;L;L;.;.
MutationTaster
Benign
0.36
P;P;P;P
PrimateAI
Benign
0.20
T
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
T
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.

Other links and lift over

dbSNP: rs700519; hg19: chr15-51507968; COSMIC: COSV53057759; COSMIC: COSV53057759; API