rs700518

Positions:

chr15-51236915-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000103.4(CYP19A1):c.240A>G(p.Val80=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,613,856 control chromosomes in the GnomAD database, including 186,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13331 hom., cov: 32)

Exomes 𝑓: 0.48 ( 172718 hom. )

Consequence

CYP19A1
NM_000103.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.655

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:53124): (MIR4713 host gene)

MIR4713HG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 15-51236915-T-C is Benign according to our data. Variant chr15-51236915-T-C is described in ClinVar as [Benign]. Clinvar id is 316477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51236915-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.655 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.504 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.240A>G	p.Val80=	synonymous_variant	3/10	ENST00000396402.6	NP_000094.2
MIR4713HG	NR_146310.1 linkuse as main transcript	n.195-41068T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6 linkuse as main transcript	c.240A>G	p.Val80=	synonymous_variant	3/10	1	NM_000103.4	ENSP00000379683	P1	P11511-1
MIR4713HG	ENST00000559909.1 linkuse as main transcript	n.195-41068T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60479

AN:

151934

Hom.:

13332

Cov.:

show subpopulations

Gnomad AFR

AF:

0.204

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.520

Gnomad EAS

AF:

0.421

Gnomad SAS

AF:

0.335

Gnomad FIN

AF:

0.492

Gnomad MID

AF:

0.350

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.417

GnomAD3 exomes

AF:

0.426

AC:

107137

AN:

251450

Hom.:

24281

AF XY:

0.432

AC XY:

58656

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.507

Gnomad EAS exome

AF:

0.436

Gnomad SAS exome

AF:

0.330

Gnomad FIN exome

AF:

0.497

Gnomad NFE exome

AF:

0.501

Gnomad OTH exome

AF:

0.455

GnomAD4 exome

AF:

0.480

AC:

701412

AN:

1461802

Hom.:

172718

Cov.:

AF XY:

0.477

AC XY:

346916

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.190

Gnomad4 AMR exome

AF:

0.303

Gnomad4 ASJ exome

AF:

0.514

Gnomad4 EAS exome

AF:

0.399

Gnomad4 SAS exome

AF:

0.335

Gnomad4 FIN exome

AF:

0.499

Gnomad4 NFE exome

AF:

0.510

Gnomad4 OTH exome

AF:

0.457

GnomAD4 genome

AF:

0.398

AC:

60485

AN:

152054

Hom.:

13331

Cov.:

AF XY:

0.395

AC XY:

29339

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.204

Gnomad4 AMR

AF:

0.343

Gnomad4 ASJ

AF:

0.520

Gnomad4 EAS

AF:

0.421

Gnomad4 SAS

AF:

0.338

Gnomad4 FIN

AF:

0.492

Gnomad4 NFE

AF:

0.508

Gnomad4 OTH

AF:

0.411

Alfa

AF:

0.477

Hom.:

42894

Bravo

AF:

0.380

Asia WGS

AF:

0.301

AC:

1050

AN:

3478

EpiCase

AF:

0.481

EpiControl

AF:

0.487

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19419293, 20981092, 16418790) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Aromatase deficiency

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
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. -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Aromatase excess syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

3.7

DANN

Benign

0.68

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.

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