rs700518

chr15-51236915-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.655

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 -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	UniProt
CYP19A1	NM_000103.4	c.240A>G	p.Val80=	synonymous_variant	3/10	ENST00000396402.6
MIR4713HG	NR_146310.1	n.195-41068T>C		intron_variant, non_coding_transcript_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60479 AN: 151934 Hom.: 13332 Cov.: 32

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

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.: 63 AF XY: 0.477 AC XY: 346916 AN XY: 727204

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.: 32 AF XY: 0.395 AC XY: 29339 AN XY: 74316

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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+	-	- -

not provided Benign:2

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	clinical testing	Invitae	Feb 01, 2024	- -

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

Other links and lift over

dbSNP: rs700518; hg19: chr15-51529112; COSMIC: COSV53058055;