rs121434534

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate

The NM_000103.4(CYP19A1):​c.1303C>T​(p.Arg435Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,588,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

CYP19A1
NM_000103.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.54
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 Likely_pathogenic. Variant got 6 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 15-51211017-G-A is Pathogenic according to our data. Variant chr15-51211017-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17815.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYP19A1NM_000103.4 linkuse as main transcriptc.1303C>T p.Arg435Cys missense_variant 10/10 ENST00000396402.6 NP_000094.2
MIR4713HGNR_146310.1 linkuse as main transcriptn.195-66966G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP19A1ENST00000396402.6 linkuse as main transcriptc.1303C>T p.Arg435Cys missense_variant 10/101 NM_000103.4 ENSP00000379683 P1P11511-1
MIR4713HGENST00000559909.1 linkuse as main transcriptn.195-66966G>A intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250788
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135502
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000557
AC:
8
AN:
1436048
Hom.:
0
Cov.:
26
AF XY:
0.00000698
AC XY:
5
AN XY:
716092
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000459
Gnomad4 OTH exome
AF:
0.0000168
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152138
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aromatase deficiency Pathogenic:2
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 15, 1993- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 435 of the CYP19A1 protein (p.Arg435Cys). This variant is present in population databases (rs121434534, gnomAD 0.006%). This missense change has been observed in individuals with aromatase deficiency (PMID: 8265607, 17164303, 23329769, 27256151). ClinVar contains an entry for this variant (Variation ID: 17815). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP19A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CYP19A1 function (PMID: 8265607, 17164303). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.86
D;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
.;.;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
3.0
M;M;M
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.5
D;D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.89
MutPred
0.94
Gain of catalytic residue at P434 (P = 0.007);Gain of catalytic residue at P434 (P = 0.007);Gain of catalytic residue at P434 (P = 0.007);
MVP
0.98
MPC
0.67
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.85
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs121434534; hg19: chr15-51503214; API