15-51329931-G-T

Variant names:

• chr15-51329931-G-T
• rs7174997
• NM_000103.4:c.-39+8564C>A

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+8564C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 152,186 control chromosomes in the GnomAD database, including 1,817 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 0.14 (1817 hom., cov: 32)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.413
• Publications: 13 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 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+8564C>A		intron	N/A	NP_000094.2
	CYP19A1	NM_031226.3		c.-147-6007C>A		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+8564C>A		intron	N/A	ENSP00000379683.1
	CYP19A1	ENST00000439712.6	TSL:1	n.-283+8564C>A		intron	N/A	ENSP00000390614.2
	CYP19A1	ENST00000557934.5	TSL:1	n.-39+8564C>A		intron	N/A	ENSP00000454004.1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21112 AN: 152068 Hom.: 1817 Cov.: 32

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0749

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.139 AC: 21110 AN: 152186 Hom.: 1817 Cov.: 32 AF XY: 0.141 AC XY: 10489 AN XY: 74410

African (AFR) AF: 0.0359 AC: 1492 AN: 41548

American (AMR) AF: 0.161 AC: 2468 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 626 AN: 3472

East Asian (EAS) AF: 0.0753 AC: 390 AN: 5182

South Asian (SAS) AF: 0.135 AC: 651 AN: 4818

European-Finnish (FIN) AF: 0.232 AC: 2456 AN: 10574

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.184 AC: 12518 AN: 67976

Other (OTH) AF: 0.162 AC: 343 AN: 2116

Alfa AF: 0.172 Hom.: 5248

Bravo AF: 0.128

Asia WGS AF: 0.124 AC: 430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.37
DANN	Benign	0.49
PhyloP100		-0.41
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: rs7174997; hg19: chr15-51622128;