Variant rs727479 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000103.4(CYP19A1):c.145+418G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 270,982 control chromosomes in the GnomAD database, including 62,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.69 ( 36079 hom., cov: 28)

Exomes 𝑓: 0.67 ( 26732 hom. )

Consequence

CYP19A1
NM_000103.4 intron

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -3.08

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 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.145+418G>T		intron_variant		ENST00000396402.6	NP_000094.2
MIR4713HG	NR_146310.1 linkuse as main transcript	n.195-35633C>A		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.145+418G>T		intron_variant		1	NM_000103.4	ENSP00000379683	P1	P11511-1
MIR4713HG	ENST00000559909.1 linkuse as main transcript	n.195-35633C>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.687

AC:

104107

AN:

151444

Hom.:

36036

Cov.:

show subpopulations

Gnomad AFR

AF:

0.784

Gnomad AMI

AF:

0.613

Gnomad AMR

AF:

0.623

Gnomad ASJ

AF:

0.676

Gnomad EAS

AF:

0.688

Gnomad SAS

AF:

0.745

Gnomad FIN

AF:

0.659

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.640

GnomAD4 exome

AF:

0.668

AC:

79742

AN:

119420

Hom.:

26732

AF XY:

0.675

AC XY:

42352

AN XY:

62766

show subpopulations

Gnomad4 AFR exome

AF:

0.789

Gnomad4 AMR exome

AF:

0.605

Gnomad4 ASJ exome

AF:

0.663

Gnomad4 EAS exome

AF:

0.696

Gnomad4 SAS exome

AF:

0.738

Gnomad4 FIN exome

AF:

0.652

Gnomad4 NFE exome

AF:

0.652

Gnomad4 OTH exome

AF:

0.656

GnomAD4 genome

AF:

0.688

AC:

104207

AN:

151562

Hom.:

36079

Cov.:

AF XY:

0.688

AC XY:

50955

AN XY:

74048

show subpopulations

Gnomad4 AFR

AF:

0.784

Gnomad4 AMR

AF:

0.622

Gnomad4 ASJ

AF:

0.676

Gnomad4 EAS

AF:

0.687

Gnomad4 SAS

AF:

0.745

Gnomad4 FIN

AF:

0.659

Gnomad4 NFE

AF:

0.647

Gnomad4 OTH

AF:

0.640

Alfa

AF:

0.655

Hom.:

16695

Bravo

AF:

0.686

Asia WGS

AF:

0.693

AC:

2411

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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 T allele was found to be associated with a dominant effect with 1) increased cumulative incidence of distant metastasis, 2) decreased overall survival,; and with a recessive effect with 3) descreased cumulative incidence of cardiovascular events (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

-0.93

CADD

Benign

0.021

DANN

Benign

0.37

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