15-51209207-C-T

Variant names:

• chr15-51209207-C-T
• rs12148604
• NM_000103.4:c.*1601G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000103.4(CYP19A1):​c.*1601G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 152,038 control chromosomes in the GnomAD database, including 16,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16474 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CYP19A1 NM_000103.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.658
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 15-51209207-C-T is Benign according to our data. Variant chr15-51209207-C-T is described in ClinVar as Benign. ClinVar VariationId is 316454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.*1601G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000396402.6	NP_000094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.*1601G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_000103.4	ENSP00000379683.1
MIR4713HG	ENST00000559909.1	n.195-68776C>T		intron_variant	Intron 1 of 2	4
MIR4713HG	ENST00000805692.1	n.279-68776C>T		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69603 AN: 151920 Hom.: 16472 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.466

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.458 AC: 69631 AN: 152038 Hom.: 16474 Cov.: 32 AF XY: 0.454 AC XY: 33739 AN XY: 74322

African (AFR) AF: 0.356 AC: 14739 AN: 41452

American (AMR) AF: 0.385 AC: 5878 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1909 AN: 3466

East Asian (EAS) AF: 0.497 AC: 2577 AN: 5180

South Asian (SAS) AF: 0.333 AC: 1607 AN: 4822

European-Finnish (FIN) AF: 0.524 AC: 5537 AN: 10574

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.527 AC: 35808 AN: 67954

Other (OTH) AF: 0.464 AC: 980 AN: 2112

Alfa AF: 0.481 Hom.: 10619

Bravo AF: 0.447

Asia WGS AF: 0.381 AC: 1325 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aromatase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.7
DANN	Benign	0.61
PhyloP100		0.66
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: rs12148604; hg19: chr15-51501404;