rs1065778

Positions:

• chr15-51228009-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000396402.6(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 ENST00000396402.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0770

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.297-76A>G		intron_variant		ENST00000396402.6	NP_000094.2
MIR4713HG	NR_146310.1	n.195-49974T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.297-76A>G		intron_variant		1	NM_000103.4	ENSP00000379683	P1
MIR4713HG	ENST00000559909.1	n.195-49974T>C		intron_variant, non_coding_transcript_variant		4

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

Gnomad4 AFR exome AF: 0.203

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.513

Gnomad4 EAS exome AF: 0.394

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.505

Gnomad4 OTH exome AF: 0.452

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

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.519

Gnomad4 EAS AF: 0.421

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.492

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.411

Alfa AF: 0.479 Hom.: 22737

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs1065778; hg19: chr15-51520206; COSMIC: COSV53058043;