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GeneBe

rs10046

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000103.4(CYP19A1):c.*19C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,434,492 control chromosomes in the GnomAD database, including 171,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14973 hom., cov: 32)
Exomes 𝑓: 0.49 ( 156938 hom. )

Consequence

CYP19A1
NM_000103.4 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.452
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)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
Variant 15-51210789-G-A is Benign according to our data. Variant chr15-51210789-G-A is described in ClinVar as [Benign]. Clinvar id is 316469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51210789-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP19A1NM_000103.4 linkuse as main transcriptc.*19C>T 3_prime_UTR_variant 10/10 ENST00000396402.6
MIR4713HGNR_146310.1 linkuse as main transcriptn.195-67194G>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.*19C>T 3_prime_UTR_variant 10/101 NM_000103.4 P1P11511-1
CYP19A1ENST00000559878.5 linkuse as main transcriptc.*19C>T 3_prime_UTR_variant 9/91 P1P11511-1
MIR4713HGENST00000559909.1 linkuse as main transcriptn.195-67194G>A intron_variant, non_coding_transcript_variant 4
CYP19A1ENST00000396404.8 linkuse as main transcriptc.*19C>T 3_prime_UTR_variant 11/112 P1P11511-1

Frequencies

GnomAD3 genomes
AF:
0.427
AC:
64910
AN:
151904
Hom.:
14970
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.249
Gnomad AMI
AF:
0.523
Gnomad AMR
AF:
0.374
Gnomad ASJ
AF:
0.551
Gnomad EAS
AF:
0.498
Gnomad SAS
AF:
0.332
Gnomad FIN
AF:
0.523
Gnomad MID
AF:
0.408
Gnomad NFE
AF:
0.526
Gnomad OTH
AF:
0.447
GnomAD3 exomes
AF:
0.451
AC:
113281
AN:
251058
Hom.:
27074
AF XY:
0.455
AC XY:
61741
AN XY:
135668
show subpopulations
Gnomad AFR exome
AF:
0.249
Gnomad AMR exome
AF:
0.317
Gnomad ASJ exome
AF:
0.534
Gnomad EAS exome
AF:
0.518
Gnomad SAS exome
AF:
0.331
Gnomad FIN exome
AF:
0.529
Gnomad NFE exome
AF:
0.519
Gnomad OTH exome
AF:
0.485
GnomAD4 exome
AF:
0.487
AC:
624570
AN:
1282470
Hom.:
156938
Cov.:
19
AF XY:
0.485
AC XY:
313680
AN XY:
647102
show subpopulations
Gnomad4 AFR exome
AF:
0.230
Gnomad4 AMR exome
AF:
0.327
Gnomad4 ASJ exome
AF:
0.540
Gnomad4 EAS exome
AF:
0.476
Gnomad4 SAS exome
AF:
0.334
Gnomad4 FIN exome
AF:
0.528
Gnomad4 NFE exome
AF:
0.514
Gnomad4 OTH exome
AF:
0.474
GnomAD4 genome
AF:
0.427
AC:
64934
AN:
152022
Hom.:
14973
Cov.:
32
AF XY:
0.424
AC XY:
31526
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.249
Gnomad4 AMR
AF:
0.374
Gnomad4 ASJ
AF:
0.551
Gnomad4 EAS
AF:
0.498
Gnomad4 SAS
AF:
0.334
Gnomad4 FIN
AF:
0.523
Gnomad4 NFE
AF:
0.526
Gnomad4 OTH
AF:
0.445
Alfa
AF:
0.505
Hom.:
34361
Bravo
AF:
0.413
Asia WGS
AF:
0.372
AC:
1293
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 22, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 10713674, 19879925) -
Aromatase deficiency Benign:1
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. -
Aromatase excess syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 01, 2021- -
Letrozole response Other:1
drug response, no assertion criteria providedresearchDepartment of Medical Oncology, IRCCS Ospedale Policlinico San MartinoMay 01, 2023This variant has been evaluated in 886 european women with hormone receptor-positive, early-stage breast cancer treated with adjuvant hormone therapy with letrozole. The minot T alelle was found to be associated with 1) increased cumulative incidence of distant metastasis, 2) decreased overall survival, 3) descreased cumulative incidence of bone fractures (which is a letrozole-related adverse event) likely associated with decreased letrozole efficacy

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
Cadd
Benign
0.62
Dann
Benign
0.31

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

LitVar

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

Other links and lift over

dbSNP: rs10046; hg19: chr15-51502986; COSMIC: COSV53058010; COSMIC: COSV53058010; API