NM_000103.4:c.-39+14212C>T

Variant names:

• chr15-51324283-G-A
• rs4774585
• NM_000103.4:c.-39+14212C>T

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+14212C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,218 control chromosomes in the GnomAD database, including 2,904 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 0.19 (2904 hom., cov: 32)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.778
• Publications: 18 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.-39+14212C>T		intron_variant	Intron 1 of 9	ENST00000396402.6	NP_000094.2
CYP19A1	NM_031226.3	c.-147-359C>T		intron_variant	Intron 1 of 10		NP_112503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.-39+14212C>T		intron_variant	Intron 1 of 9	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28303 AN: 152100 Hom.: 2907 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.186 AC: 28310 AN: 152218 Hom.: 2904 Cov.: 32 AF XY: 0.184 AC XY: 13663 AN XY: 74418

African (AFR) AF: 0.149 AC: 6205 AN: 41522

American (AMR) AF: 0.263 AC: 4028 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 814 AN: 3472

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5190

South Asian (SAS) AF: 0.191 AC: 919 AN: 4812

European-Finnish (FIN) AF: 0.133 AC: 1410 AN: 10590

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14253 AN: 68004

Other (OTH) AF: 0.197 AC: 417 AN: 2116

Alfa AF: 0.205 Hom.: 8982

Bravo AF: 0.197

Asia WGS AF: 0.0970 AC: 336 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.32
DANN	Benign	0.31
PhyloP100		-0.78
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: rs4774585; hg19: chr15-51616480;