rs700519

chr15-51215771-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.790C>T(p.Arg264Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,613,786 control chromosomes in the GnomAD database, including 5,264 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.081 (861 hom., cov: 33)
  • Exomes 𝑓: 0.052 (4403 hom.)
• Consequence: CYP19A1 NM_000103.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.17

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 (MetaRNN=0.0016607046).
• BP6: Variant 15-51215771-G-A is Benign according to our data. Variant chr15-51215771-G-A is described in ClinVar as [Benign]. Clinvar id is 137064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP19A1	NM_000103.4	c.790C>T	p.Arg264Cys	missense_variant	7/10	ENST00000396402.6
MIR4713HG	NR_146310.1	n.195-62212G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP19A1	ENST00000396402.6	c.790C>T	p.Arg264Cys	missense_variant	7/10	1	NM_000103.4	P1
MIR4713HG	ENST00000559909.1	n.195-62212G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0807 AC: 12262 AN: 152018 Hom.: 860 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0456

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0761 AC: 19115 AN: 251272 Hom.: 1433 AF XY: 0.0792 AC XY: 10760 AN XY: 135800

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.0589

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.0443

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0487

GnomAD4 exome AF: 0.0518 AC: 75646 AN: 1461650 Hom.: 4403 Cov.: 34 AF XY: 0.0557 AC XY: 40531 AN XY: 727120

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.0565

Gnomad4 ASJ exome AF: 0.0353

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.0413

Gnomad4 NFE exome AF: 0.0312

Gnomad4 OTH exome AF: 0.0565

GnomAD4 genome AF: 0.0807 AC: 12276 AN: 152136 Hom.: 861 Cov.: 33 AF XY: 0.0834 AC XY: 6205 AN XY: 74378

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.0422

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.0456

Gnomad4 NFE AF: 0.0333

Gnomad4 OTH AF: 0.0516

Alfa AF: 0.0446 Hom.: 517

Bravo AF: 0.0800

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.164 AC: 721

ESP6500EA AF: 0.0330 AC: 283

ExAC AF: 0.0796 AC: 9662

Asia WGS AF: 0.200 AC: 694 AN: 3476

EpiCase AF: 0.0328

EpiControl AF: 0.0286

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aromatase deficiency Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;D;D;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;.;.
MutationTaster	Benign	0.36	P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.044	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;.
Polyphen		0.011	B;B;B;.;.
Vest4		0.083
MPC		0.17
ClinPred		0.025	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.39

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: rs700519; hg19: chr15-51507968; COSMIC: COSV53057759; COSMIC: COSV53057759;