rs28757184

Positions:

Variant summary

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

The NM_000103.4(CYP19A1):c.602C>T(p.Thr201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,614,100 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 120 hom., cov: 32)

Exomes 𝑓: 0.030 ( 750 hom. )

Consequence

CYP19A1
NM_000103.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0770

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:):

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=0.0063601136).

BP6

Variant 15-51222375-G-A is Benign according to our data. Variant chr15-51222375-G-A is described in ClinVar as [Benign]. Clinvar id is 316476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51222375-G-A is described in Lovd as [Benign]. Variant chr15-51222375-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0558 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.602C>T	p.Thr201Met	missense_variant	5/10	ENST00000396402.6	NP_000094.2	P11511-1A0A024R5S8Q8IYG4Q8TCA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6 linkuse as main transcript	c.602C>T	p.Thr201Met	missense_variant	5/10	1	NM_000103.4	ENSP00000379683.1		P11511-1

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5469

AN:

152110

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0577

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0254

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0392

GnomAD3 exomes

AF:

0.0236

AC:

5943

AN:

251336

Hom.:

101

AF XY:

0.0226

AC XY:

3072

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.0559

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00477

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.0310

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0299

AC:

43718

AN:

1461872

Hom.:

750

Cov.:

AF XY:

0.0290

AC XY:

21106

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0585

Gnomad4 AMR exome

AF:

0.0200

Gnomad4 ASJ exome

AF:

0.0266

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00492

Gnomad4 FIN exome

AF:

0.0138

Gnomad4 NFE exome

AF:

0.0335

Gnomad4 OTH exome

AF:

0.0271

GnomAD4 genome

AF:

0.0359

AC:

5472

AN:

152228

Hom.:

120

Cov.:

AF XY:

0.0339

AC XY:

2526

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0577

Gnomad4 AMR

AF:

0.0256

Gnomad4 ASJ

AF:

0.0254

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00519

Gnomad4 FIN

AF:

0.0128

Gnomad4 NFE

AF:

0.0344

Gnomad4 OTH

AF:

0.0388

Alfa

AF:

0.0317

Hom.:

216

Bravo

AF:

0.0385

TwinsUK

AF:

0.0329

AC:

122

ALSPAC

AF:

0.0332

AC:

128

ESP6500AA

AF:

0.0617

AC:

271

ESP6500EA

AF:

0.0356

AC:

306

ExAC

AF:

0.0242

AC:

2943

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16424004, 19470632) -

Aromatase deficiency

Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 25, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.18

DANN

Benign

0.95

DEOGEN2

Benign

0.30

T;T;T;T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.67

.;.;T;T;T;.;T

MetaRNN

Benign

0.0064

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;N;N;.;.;N;N

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.78

N;N;N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.064

T;T;T;T;T;T;T

Sift4G

Uncertain

0.037

D;D;D;.;D;T;T

Polyphen

0.0090

B;B;B;.;.;.;.

Vest4

0.073

MPC

0.13

ClinPred

0.0016

GERP RS

-3.7

Varity_R

0.029

gMVP

0.49

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.

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