rs1961177

Variant names:

• chr15-51332881-C-T
• rs1961177
• NM_000103.4:c.-39+5614G>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+5614G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 152,088 control chromosomes in the GnomAD database, including 4,770 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 0.21 (4770 hom., cov: 32)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.-39+5614G>A		intron_variant	Intron 1 of 9	ENST00000396402.6	NP_000094.2
CYP19A1	NM_031226.3	c.-148+5614G>A		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+5614G>A		intron_variant	Intron 1 of 9	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31999 AN: 151970 Hom.: 4754 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.0637

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.198

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

GnomAD4 genome AF: 0.211 AC: 32068 AN: 152088 Hom.: 4770 Cov.: 32 AF XY: 0.210 AC XY: 15635 AN XY: 74382

African (AFR) AF: 0.419 AC: 17364 AN: 41438

American (AMR) AF: 0.174 AC: 2657 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 484 AN: 3468

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5164

South Asian (SAS) AF: 0.260 AC: 1251 AN: 4816

European-Finnish (FIN) AF: 0.0637 AC: 675 AN: 10596

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 7993 AN: 67998

Other (OTH) AF: 0.202 AC: 427 AN: 2114

Alfa AF: 0.173 Hom.: 555

Bravo AF: 0.227

Asia WGS AF: 0.290 AC: 1010 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.50
DANN	Benign	0.36
PhyloP100		-0.35
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: rs1961177; hg19: chr15-51625078;