rs2304463

Variant names:

• chr15-51215923-A-C
• rs2304463
• NM_000103.4:c.744-106T>G

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.744-106T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,567,302 control chromosomes in the GnomAD database, including 200,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15057 hom., cov: 32)
  • Exomes 𝑓: 0.51 (184961 hom.)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• Publications: 6 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=-0.91).
• BP6: Variant 15-51215923-A-C is Benign according to our data. Variant chr15-51215923-A-C is described in ClinVar as Benign. ClinVar VariationId is 1241371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.744-106T>G		intron_variant	Intron 6 of 9	ENST00000396402.6	NP_000094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.744-106T>G		intron_variant	Intron 6 of 9	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64811 AN: 151940 Hom.: 15059 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.450

GnomAD4 exome AF: 0.506 AC: 716531 AN: 1415244 Hom.: 184961 Cov.: 27 AF XY: 0.504 AC XY: 354109 AN XY: 702366

African (AFR) AF: 0.219 AC: 7066 AN: 32200

American (AMR) AF: 0.333 AC: 13355 AN: 40096

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14213 AN: 25522

East Asian (EAS) AF: 0.492 AC: 18696 AN: 38032

South Asian (SAS) AF: 0.388 AC: 31956 AN: 82408

European-Finnish (FIN) AF: 0.527 AC: 21281 AN: 40354

Middle Eastern (MID) AF: 0.431 AC: 2431 AN: 5634

European-Non Finnish (NFE) AF: 0.530 AC: 578648 AN: 1092058

Other (OTH) AF: 0.490 AC: 28885 AN: 58940

GnomAD4 genome AF: 0.426 AC: 64823 AN: 152058 Hom.: 15057 Cov.: 32 AF XY: 0.424 AC XY: 31532 AN XY: 74306

African (AFR) AF: 0.233 AC: 9669 AN: 41506

American (AMR) AF: 0.372 AC: 5686 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1961 AN: 3470

East Asian (EAS) AF: 0.515 AC: 2659 AN: 5168

South Asian (SAS) AF: 0.393 AC: 1889 AN: 4812

European-Finnish (FIN) AF: 0.524 AC: 5517 AN: 10538

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35893 AN: 67970

Other (OTH) AF: 0.448 AC: 945 AN: 2110

Alfa AF: 0.476 Hom.: 2664

Bravo AF: 0.410

Asia WGS AF: 0.393 AC: 1367 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.32
PhyloP100		-1.1
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: rs2304463; hg19: chr15-51508120; COSMIC: COSV53056973; COSMIC: COSV53056973;