Genetic Variant NM_000103.4:c.-39+16786G>C (chr15-51321709-C-G) – 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+16786G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 152,148 control chromosomes in the GnomAD database, including 26,944 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 0.56 ( 26939 hom., cov: 32)

Exomes 𝑓: 0.38 ( 5 hom. )

Consequence

CYP19A1
NM_000103.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.429

Publications

10 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:

Genome browser will be placed here

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=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4 link	c.-39+16786G>C	intron_variant	Intron 1 of 9	ENST00000396402.6	NP_000094.2	P11511-1A0A024R5S8Q8IYG4Q8TCA4
LOC112268146	XR_002957708.2 link	n.1213C>G	non_coding_transcript_exon_variant	Exon 2 of 2
CYP19A1	NM_001347248.1 link	c.-39+2107G>C	intron_variant	Intron 1 of 9		NP_001334177.1	P11511-1A0A024R5S8
CYP19A1	NM_031226.3 link	c.-39+2107G>C	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+16786G>C		intron_variant	Intron 1 of 9	1	NM_000103.4	ENSP00000379683.1		P11511-1

Frequencies

GnomAD3 genomes

AF:

0.564

AC:

85753

AN:

151938

Hom.:

26866

Cov.:

show subpopulations

Gnomad AFR

AF:

0.843

Gnomad AMI

AF:

0.384

Gnomad AMR

AF:

0.588

Gnomad ASJ

AF:

0.434

Gnomad EAS

AF:

0.584

Gnomad SAS

AF:

0.508

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.553

GnomAD4 exome

AF:

0.380

AC:

AN:

Hom.:

Cov.:

AF XY:

0.394

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.354

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.565

AC:

85886

AN:

152056

Hom.:

26939

Cov.:

AF XY:

0.559

AC XY:

41509

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.843

AC:

34979

AN:

41498

American (AMR)

AF:

0.589

AC:

9005

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.434

AC:

1504

AN:

3464

East Asian (EAS)

AF:

0.585

AC:

3008

AN:

5146

South Asian (SAS)

AF:

0.507

AC:

2441

AN:

4810

European-Finnish (FIN)

AF:

0.306

AC:

3232

AN:

10566

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.443

AC:

30091

AN:

67972

Other (OTH)

AF:

0.556

AC:

1176

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1669

3338

5008

6677

8346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

698

1396

2094

2792

3490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.482

Hom.:

2307

Bravo

AF:

0.604

Asia WGS

AF:

0.586

AC:

2036

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.6

(source)

DANN

Benign

0.77

PhyloP100

-0.43

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over