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GeneBe

rs4646

Variant summary

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

The NM_000103.4(CYP19A1):c.*161T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 752,108 control chromosomes in the GnomAD database, including 187,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37731 hom., cov: 32)
Exomes 𝑓: 0.70 ( 149410 hom. )

Consequence

CYP19A1
NM_000103.4 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.27
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 (BayesDel_noAF=-0.93).
BP6
Variant 15-51210647-A-C is Benign according to our data. Variant chr15-51210647-A-C is described in ClinVar as [Benign]. Clinvar id is 316467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51210647-A-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP19A1NM_000103.4 linkuse as main transcriptc.*161T>G 3_prime_UTR_variant 10/10 ENST00000396402.6
MIR4713HGNR_146310.1 linkuse as main transcriptn.195-67336A>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP19A1ENST00000396402.6 linkuse as main transcriptc.*161T>G 3_prime_UTR_variant 10/101 NM_000103.4 P1P11511-1
CYP19A1ENST00000559878.5 linkuse as main transcriptc.*161T>G 3_prime_UTR_variant 9/91 P1P11511-1
MIR4713HGENST00000559909.1 linkuse as main transcriptn.195-67336A>C intron_variant, non_coding_transcript_variant 4
CYP19A1ENST00000396404.8 linkuse as main transcriptc.*161T>G 3_prime_UTR_variant 11/112 P1P11511-1

Frequencies

GnomAD3 genomes
AF:
0.702
AC:
106604
AN:
151928
Hom.:
37705
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.693
Gnomad AMI
AF:
0.644
Gnomad AMR
AF:
0.571
Gnomad ASJ
AF:
0.769
Gnomad EAS
AF:
0.682
Gnomad SAS
AF:
0.623
Gnomad FIN
AF:
0.720
Gnomad MID
AF:
0.759
Gnomad NFE
AF:
0.738
Gnomad OTH
AF:
0.681
GnomAD3 exomes
AF:
0.672
AC:
147573
AN:
219628
Hom.:
50443
AF XY:
0.679
AC XY:
81398
AN XY:
119940
show subpopulations
Gnomad AFR exome
AF:
0.695
Gnomad AMR exome
AF:
0.485
Gnomad ASJ exome
AF:
0.749
Gnomad EAS exome
AF:
0.674
Gnomad SAS exome
AF:
0.626
Gnomad FIN exome
AF:
0.716
Gnomad NFE exome
AF:
0.728
Gnomad OTH exome
AF:
0.701
GnomAD4 exome
AF:
0.701
AC:
420906
AN:
600062
Hom.:
149410
Cov.:
4
AF XY:
0.702
AC XY:
230169
AN XY:
327918
show subpopulations
Gnomad4 AFR exome
AF:
0.685
Gnomad4 AMR exome
AF:
0.496
Gnomad4 ASJ exome
AF:
0.754
Gnomad4 EAS exome
AF:
0.707
Gnomad4 SAS exome
AF:
0.627
Gnomad4 FIN exome
AF:
0.720
Gnomad4 NFE exome
AF:
0.735
Gnomad4 OTH exome
AF:
0.708
GnomAD4 genome
AF:
0.702
AC:
106677
AN:
152046
Hom.:
37731
Cov.:
32
AF XY:
0.698
AC XY:
51840
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.693
Gnomad4 AMR
AF:
0.570
Gnomad4 ASJ
AF:
0.769
Gnomad4 EAS
AF:
0.682
Gnomad4 SAS
AF:
0.625
Gnomad4 FIN
AF:
0.720
Gnomad4 NFE
AF:
0.738
Gnomad4 OTH
AF:
0.682
Alfa
AF:
0.726
Hom.:
73977
Bravo
AF:
0.688
Asia WGS
AF:
0.639
AC:
2224
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Aromatase deficiency Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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. -
Benign, no assertion criteria providedclinical testingNatera, Inc.Dec 06, 2019- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJun 26, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
Cadd
Benign
0.10
Dann
Benign
0.46

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: rs4646; hg19: chr15-51502844; COSMIC: COSV53058004; COSMIC: COSV53058004; API