rs1065778

Variant names:

• chr15-51228009-T-C
• rs1065778
• NM_000103.4:c.297-76A>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.297-76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 808,196 control chromosomes in the GnomAD database, including 84,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13348 hom., cov: 32)
  • Exomes 𝑓: 0.45 (70814 hom.)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0770
• Publications: 26 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=-0.82).
• BP6: Variant 15-51228009-T-C is Benign according to our data. Variant chr15-51228009-T-C is described in ClinVar as Benign. ClinVar VariationId is 1251612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.297-76A>G		intron_variant	Intron 3 of 9	ENST00000396402.6	NP_000094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.297-76A>G		intron_variant	Intron 3 of 9	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60515 AN: 151926 Hom.: 13350 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.417

GnomAD4 exome AF: 0.455 AC: 298541 AN: 656152 Hom.: 70814 AF XY: 0.454 AC XY: 161530 AN XY: 355972

African (AFR) AF: 0.203 AC: 3684 AN: 18158

American (AMR) AF: 0.302 AC: 13142 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 10791 AN: 21034

East Asian (EAS) AF: 0.394 AC: 14129 AN: 35890

South Asian (SAS) AF: 0.336 AC: 23465 AN: 69826

European-Finnish (FIN) AF: 0.497 AC: 25802 AN: 51864

Middle Eastern (MID) AF: 0.379 AC: 1529 AN: 4032

European-Non Finnish (NFE) AF: 0.505 AC: 190688 AN: 377924

Other (OTH) AF: 0.452 AC: 15311 AN: 33882

GnomAD4 genome AF: 0.398 AC: 60522 AN: 152044 Hom.: 13348 Cov.: 32 AF XY: 0.395 AC XY: 29345 AN XY: 74322

African (AFR) AF: 0.204 AC: 8458 AN: 41486

American (AMR) AF: 0.343 AC: 5241 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1801 AN: 3468

East Asian (EAS) AF: 0.421 AC: 2176 AN: 5166

South Asian (SAS) AF: 0.338 AC: 1627 AN: 4810

European-Finnish (FIN) AF: 0.492 AC: 5183 AN: 10538

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34589 AN: 67972

Other (OTH) AF: 0.411 AC: 868 AN: 2110

Alfa AF: 0.469 Hom.: 28006

Bravo AF: 0.380

Asia WGS AF: 0.300 AC: 1046 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.62
PhyloP100		0.077
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: rs1065778; hg19: chr15-51520206; COSMIC: COSV53058043;