Genetic Variant CYP19A1:c.146-59A>G (chr15-51237068-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000103.4(CYP19A1):c.146-59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,594,836 control chromosomes in the GnomAD database, including 184,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13322 hom., cov: 33)

Exomes 𝑓: 0.48 ( 170720 hom. )

Consequence

CYP19A1
NM_000103.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.259

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 15-51237068-T-C is Benign according to our data. Variant chr15-51237068-T-C is described in ClinVar as [Benign]. Clinvar id is 1271622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4 link	c.146-59A>G		intron_variant	Intron 2 of 9	ENST00000396402.6	NP_000094.2	P11511-1A0A024R5S8Q8IYG4Q8TCA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6 link	c.146-59A>G		intron_variant	Intron 2 of 9	1	NM_000103.4	ENSP00000379683.1		P11511-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60468

AN:

152006

Hom.:

13323

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:

0.491

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.416

GnomAD4 exome

AF:

0.481

AC:

693328

AN:

1442710

Hom.:

170720

AF XY:

0.478

AC XY:

343102

AN XY:

718214

show subpopulations

Gnomad4 AFR exome

AF:

0.191

Gnomad4 AMR exome

AF:

0.304

Gnomad4 ASJ exome

AF:

0.515

Gnomad4 EAS exome

AF:

0.399

Gnomad4 SAS exome

AF:

0.335

Gnomad4 FIN exome

AF:

0.499

Gnomad4 NFE exome

AF:

0.511

Gnomad4 OTH exome

AF:

0.458

GnomAD4 genome

AF:

0.398

AC:

60472

AN:

152126

Hom.:

13322

Cov.:

AF XY:

0.394

AC XY:

29320

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.203

Gnomad4 AMR

AF:

0.343

Gnomad4 ASJ

AF:

0.520

Gnomad4 EAS

AF:

0.420

Gnomad4 SAS

AF:

0.338

Gnomad4 FIN

AF:

0.491

Gnomad4 NFE

AF:

0.508

Gnomad4 OTH

AF:

0.410

Alfa

AF:

0.442

Hom.:

3269

Bravo

AF:

0.380

Asia WGS

AF:

0.299

AC:

1043

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.8

DANN

Benign

0.60

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.

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