15-51323419-T-C

Variant names:

• chr15-51323419-T-C
• rs2445761
• NM_000103.4:c.-39+15076A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000103.4(CYP19A1):​c.-39+15076A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 151,706 control chromosomes in the GnomAD database, including 26,964 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (26964 hom., cov: 32)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• aromatase excess syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.-39+15076A>G		intron_variant	Intron 1 of 9	ENST00000396402.6	NP_000094.2
CYP19A1	NM_001347248.1	c.-39+397A>G		intron_variant	Intron 1 of 9		NP_001334177.1
CYP19A1	NM_031226.3	c.-39+397A>G		intron_variant	Intron 2 of 10		NP_112503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.-39+15076A>G		intron_variant	Intron 1 of 9	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85782 AN: 151596 Hom.: 26892 Cov.: 32

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.362

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.566 AC: 85914 AN: 151706 Hom.: 26964 Cov.: 32 AF XY: 0.560 AC XY: 41496 AN XY: 74076

African (AFR) AF: 0.843 AC: 34966 AN: 41454

American (AMR) AF: 0.589 AC: 8991 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1507 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3050 AN: 5168

South Asian (SAS) AF: 0.511 AC: 2459 AN: 4808

European-Finnish (FIN) AF: 0.311 AC: 3209 AN: 10308

Middle Eastern (MID) AF: 0.354 AC: 102 AN: 288

European-Non Finnish (NFE) AF: 0.443 AC: 30104 AN: 67942

Other (OTH) AF: 0.559 AC: 1174 AN: 2102

Alfa AF: 0.478 Hom.: 11254

Bravo AF: 0.604

Asia WGS AF: 0.585 AC: 2032 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.53
DANN	Benign	0.28
PhyloP100		-0.32
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

Other links and lift over

dbSNP: rs2445761; hg19: chr15-51615616;