ENST00000405913.7:c.628G>A

Variant names:

• chr15-51222349-C-T
• rs121434538
• ENST00000405913.7:c.628G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The ENST00000405913.7(CYP19A1):​c.628G>A​(p.Gly210Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G210G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CYP19A1 ENST00000405913.7 missense
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.56
• Publications: 12 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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-51222349-C-T is Pathogenic according to our data. Variant chr15-51222349-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000405913.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	NM_000103.4	MANE Select	c.628G>A	p.Glu210Lys	missense splice_region	Exon 5 of 10	NP_000094.2
	CYP19A1	NM_001347248.1		c.628G>A	p.Glu210Lys	missense splice_region	Exon 5 of 10	NP_001334177.1	P11511-1
	CYP19A1	NM_001347249.2		c.628G>A	p.Glu210Lys	missense splice_region	Exon 5 of 10	NP_001334178.1	P11511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000405913.7	TSL:1	c.628G>A	p.Gly210Ser	missense	Exon 4 of 4	ENSP00000383930.3	P11511-2
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.628G>A	p.Glu210Lys	missense splice_region	Exon 5 of 10	ENSP00000379683.1	P11511-1
	CYP19A1	ENST00000559878.5	TSL:1	c.628G>A	p.Glu210Lys	missense splice_region	Exon 4 of 9	ENSP00000453149.1	P11511-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251154 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000493 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Aromatase deficiency (1)
1	-	-	Aromatase deficiency;C1970109:Aromatase excess syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	56
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.81		Gain of ubiquitination at E210 (P = 0.0177)
MVP		0.86
MPC		0.61
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.72
gMVP		0.82
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434538; hg19: chr15-51514546; COSMIC: COSV108071386; COSMIC: COSV108071386;