15-51222375-G-A

Position:

• chr15-51222375-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.602C>T​(p.Thr201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,614,100 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T201T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (120 hom., cov: 32)
  • Exomes 𝑓: 0.030 (750 hom.)
• Consequence: CYP19A1 NM_000103.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0770

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=0.0063601136).
• BP6: Variant 15-51222375-G-A is Benign according to our data. Variant chr15-51222375-G-A is described in ClinVar as [Benign]. Clinvar id is 316476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51222375-G-A is described in Lovd as [Benign]. Variant chr15-51222375-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP19A1	NM_000103.4	c.602C>T	p.Thr201Met	missense_variant	5/10	ENST00000396402.6
MIR4713HG	NR_146310.1	n.195-55608G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP19A1	ENST00000396402.6	c.602C>T	p.Thr201Met	missense_variant	5/10	1	NM_000103.4	P1
MIR4713HG	ENST00000559909.1	n.195-55608G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5469 AN: 152110 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0236 AC: 5943 AN: 251336 Hom.: 101 AF XY: 0.0226 AC XY: 3072 AN XY: 135836

Gnomad AFR exome AF: 0.0559

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0310

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0299 AC: 43718 AN: 1461872 Hom.: 750 Cov.: 31 AF XY: 0.0290 AC XY: 21106 AN XY: 727238

Gnomad4 AFR exome AF: 0.0585

Gnomad4 AMR exome AF: 0.0200

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00492

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.0335

Gnomad4 OTH exome AF: 0.0271

GnomAD4 genome AF: 0.0359 AC: 5472 AN: 152228 Hom.: 120 Cov.: 32 AF XY: 0.0339 AC XY: 2526 AN XY: 74424

Gnomad4 AFR AF: 0.0577

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0254

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0317 Hom.: 216

Bravo AF: 0.0385

TwinsUK AF: 0.0329 AC: 122

ALSPAC AF: 0.0332 AC: 128

ESP6500AA AF: 0.0617 AC: 271

ESP6500EA AF: 0.0356 AC: 306

ExAC AF: 0.0242 AC: 2943

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.0322

EpiControl AF: 0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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.	Nov 25, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16424004, 19470632) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.18
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T;T;T;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.67	.;.;T;T;T;.;T
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;N;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.78	N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.064	T;T;T;T;T;T;T
Sift4G	Uncertain	0.037	D;D;D;.;D;T;T
Polyphen		0.0090	B;B;B;.;.;.;.
Vest4		0.073
MPC		0.13
ClinPred		0.0016	T
GERP RS		-3.7
Varity_R		0.029
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28757184; hg19: chr15-51514572;