15-51210789-G-A

Position:

chr15-51210789-G-A

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

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O: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]

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=-0.91).

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	Protein	UniProt
CYP19A1	NM_000103.4 linkuse as main transcript	c.*19C>T		3_prime_UTR_variant	10/10	ENST00000396402.6	NP_000094.2
MIR4713HG	NR_146310.1 linkuse as main transcript	n.195-67194G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6 linkuse as main transcript	c.*19C>T	3_prime_UTR_variant	10/10	1	NM_000103.4	ENSP00000379683	P1	P11511-1
CYP19A1	ENST00000559878.5 linkuse as main transcript	c.*19C>T	3_prime_UTR_variant	9/9	1		ENSP00000453149	P1	P11511-1
MIR4713HG	ENST00000559909.1 linkuse as main transcript	n.195-67194G>A	intron_variant, non_coding_transcript_variant		4
CYP19A1	ENST00000396404.8 linkuse as main transcript	c.*19C>T	3_prime_UTR_variant	11/11	2		ENSP00000379685	P1	P11511-1

Frequencies

GnomAD3 genomes

AF:

0.427

AC:

64910

AN:

151904

Hom.:

14970

Cov.:

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.:

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.:

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:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 10713674, 19879925) -

not specified

Benign:2

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

Aromatase deficiency

Benign:1

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. -

Aromatase excess syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Letrozole response

Other:1

drug response, no assertion criteria provided

research

Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino

May 01, 2023

This 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.

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