rs749292

Variant names:

• chr15-51266534-G-A
• rs749292
• NM_000103.4:c.-38-23584C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_000103.4(CYP19A1):c.-38-23584C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.441 (AC=67,062) in the gnomAD database across 152,100 control chromosomes, including 14,952 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.472. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (14952 hom., cov: 33)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.574
• Publications: 61 publications found

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 Gene-Disease associations (from GenCC):

• aromatase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Natera, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• aromatase excess syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -12 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4717 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000103.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	NM_000103.4	MANE Select	c.-38-23584C>T		intron	N/A	NP_000094.2
	CYP19A1	NM_001347248.1		c.-38-23584C>T		intron	N/A	NP_001334177.1	P11511-1
	CYP19A1	NM_001347249.2		c.-38-23584C>T		intron	N/A	NP_001334178.1	P11511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.-38-23584C>T		intron	N/A	ENSP00000379683.1	P11511-1
	CYP19A1	ENST00000439712.6	TSL:1	n.-282-10773C>T		intron	N/A	ENSP00000390614.2	E7EQ08
	CYP19A1	ENST00000557934.5	TSL:1	n.-38-23584C>T		intron	N/A	ENSP00000454004.1	E7EQ08

Frequencies

GnomAD3 genomes AF: 0.441 AC: 67030 AN: 151982 Hom.: 14951 Cov.: 33

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.440

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.441 AC: 67062 AN: 152100 Hom.: 14952 Cov.: 33 AF XY: 0.435 AC XY: 32352 AN XY: 74350

African (AFR) AF: 0.477 AC: 19796 AN: 41478

American (AMR) AF: 0.362 AC: 5535 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1721 AN: 3470

East Asian (EAS) AF: 0.446 AC: 2305 AN: 5172

South Asian (SAS) AF: 0.344 AC: 1656 AN: 4814

European-Finnish (FIN) AF: 0.429 AC: 4540 AN: 10572

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30037 AN: 67976

Other (OTH) AF: 0.436 AC: 922 AN: 2114

Alfa AF: 0.439 Hom.: 63329

Bravo AF: 0.438

Asia WGS AF: 0.368 AC: 1280 AN: 3478

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.356 AC: 43766 AN: 122822

Turkish Variome AF: 0.389 AC: 601 AN: 1544 Hom.: 124

WBBC (Westlake BioBank for Chinese) pilot AF: 0.473 AC: 4241 AN: 8960 Hom.: 1030

ABraOM SABE-WGS-1171 AF: 0.419 AC: 981 AN: 2342 Hom.: 204

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.6
DANN	Benign	0.65
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs749292;

hg19: chr15-51558731;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar