Genetic Variant CYP19A1:c.-39+16881A>G (chr15-51321614-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000103.4(CYP19A1):c.-39+16881A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,120 control chromosomes in the GnomAD database, including 12,917 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 0.40 ( 12917 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

CYP19A1
NM_000103.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.607

Publications

17 publications found

Variant links:

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 links:

MIR4713HG (HGNC:53124): (MIR4713 host gene)

MIR4713HG links:

LOC112268146 (HGNC:):

LOC112268146 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4 link	c.-39+16881A>G	intron_variant	Intron 1 of 9	ENST00000396402.6	NP_000094.2	P11511-1A0A024R5S8Q8IYG4Q8TCA4
LOC112268146	XR_002957708.2 link	n.1118T>C	non_coding_transcript_exon_variant	Exon 2 of 2
CYP19A1	NM_001347248.1 link	c.-39+2202A>G	intron_variant	Intron 1 of 9		NP_001334177.1	P11511-1A0A024R5S8
CYP19A1	NM_031226.3 link	c.-39+2202A>G	intron_variant	Intron 2 of 10		NP_112503.1	P11511-1A0A024R5S8Q05CU4A8K6W3Q8TCA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6 link	c.-39+16881A>G		intron_variant	Intron 1 of 9	1	NM_000103.4	ENSP00000379683.1		P11511-1

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61416

AN:

152000

Hom.:

12880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.281

Gnomad AMR

AF:

0.462

Gnomad ASJ

AF:

0.403

Gnomad EAS

AF:

0.299

Gnomad SAS

AF:

0.470

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.349

Gnomad NFE

AF:

0.375

Gnomad OTH

AF:

0.416

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.404

AC:

61503

AN:

152120

Hom.:

12917

Cov.:

AF XY:

0.400

AC XY:

29774

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.485

AC:

20123

AN:

41470

American (AMR)

AF:

0.464

AC:

7089

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.403

AC:

1397

AN:

3470

East Asian (EAS)

AF:

0.299

AC:

1544

AN:

5168

South Asian (SAS)

AF:

0.469

AC:

2260

AN:

4822

European-Finnish (FIN)

AF:

0.221

AC:

2347

AN:

10598

Middle Eastern (MID)

AF:

0.339

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.375

AC:

25508

AN:

67986

Other (OTH)

AF:

0.417

AC:

880

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1893

3787

5680

7574

9467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.294

Hom.:

992

Bravo

AF:

0.428

Asia WGS

AF:

0.428

AC:

1488

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

4.9

(source)

DANN

Benign

0.68

PhyloP100

0.61

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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15-51321614-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over