15-51334354-A-G

Variant names:

• chr15-51334354-A-G
• rs11070843
• NM_000103.4:c.-39+4141T>C

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+4141T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,202 control chromosomes in the GnomAD database, including 2,039 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 0.16 (2039 hom., cov: 32)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 7 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=-0.74).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	NM_000103.4	MANE Select	c.-39+4141T>C		intron	N/A	NP_000094.2
	CYP19A1	NM_031226.3		c.-148+4141T>C		intron	N/A	NP_112503.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.-39+4141T>C		intron	N/A	ENSP00000379683.1
	CYP19A1	ENST00000439712.6	TSL:1	n.-283+4141T>C		intron	N/A	ENSP00000390614.2
	CYP19A1	ENST00000557934.5	TSL:1	n.-39+4141T>C		intron	N/A	ENSP00000454004.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23618 AN: 152084 Hom.: 2027 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.164

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

GnomAD4 genome AF: 0.156 AC: 23678 AN: 152202 Hom.: 2039 Cov.: 32 AF XY: 0.157 AC XY: 11667 AN XY: 74418

African (AFR) AF: 0.225 AC: 9346 AN: 41506

American (AMR) AF: 0.154 AC: 2363 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3466

East Asian (EAS) AF: 0.206 AC: 1065 AN: 5172

South Asian (SAS) AF: 0.260 AC: 1253 AN: 4822

European-Finnish (FIN) AF: 0.0633 AC: 672 AN: 10612

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 7992 AN: 68006

Other (OTH) AF: 0.168 AC: 355 AN: 2116

Alfa AF: 0.127 Hom.: 235

Bravo AF: 0.165

Asia WGS AF: 0.288 AC: 1003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.064
DANN	Benign	0.77
PhyloP100		-1.2
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: rs11070843; hg19: chr15-51626551;