rs10046

Positions:

• chr15-51210789-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.452

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]

MIR4713HG (HGNC:53124): (MIR4713 host gene)

ACMG classification

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	c.*19C>T		3_prime_UTR_variant	10/10	ENST00000396402.6	NP_000094.2
MIR4713HG	NR_146310.1	n.195-67194G>A		intron_variant, non_coding_transcript_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64910 AN: 151904 Hom.: 14970 Cov.: 32

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

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.: 19 AF XY: 0.485 AC XY: 313680 AN XY: 647102

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.: 32 AF XY: 0.424 AC XY: 31526 AN XY: 74284

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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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

Other links and lift over

dbSNP: rs10046; hg19: chr15-51502986; COSMIC: COSV53058010; COSMIC: COSV53058010;