15-51212358-TG-T

Variant names:

• chr15-51212358-TG-T
• rs786205108
• NM_000103.4:c.1224delC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000103.4(CYP19A1):​c.1224delC​(p.Lys409AsnfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P408P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP19A1 NM_000103.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.380
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-51212358-TG-T is Pathogenic according to our data. Variant chr15-51212358-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17819.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000103.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	NM_000103.4	MANE Select	c.1224delC	p.Lys409AsnfsTer37	frameshift	Exon 9 of 10	NP_000094.2
	CYP19A1	NM_001347248.1		c.1224delC	p.Lys409AsnfsTer37	frameshift	Exon 9 of 10	NP_001334177.1
	CYP19A1	NM_001347249.2		c.1224delC	p.Lys409AsnfsTer37	frameshift	Exon 9 of 10	NP_001334178.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.1224delC	p.Lys409AsnfsTer37	frameshift	Exon 9 of 10	ENSP00000379683.1
	CYP19A1	ENST00000559878.5	TSL:1	c.1224delC	p.Lys409AsnfsTer37	frameshift	Exon 8 of 9	ENSP00000453149.1
	CYP19A1	ENST00000396404.8	TSL:2	c.1224delC	p.Lys409AsnfsTer37	frameshift	Exon 10 of 11	ENSP00000379685.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aromatase deficiency Pathogenic:1

Jun 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs786205108; hg19: chr15-51504555;