rs4324076

Positions:

• chr15-51218671-A-C
• chr15-51218671-A-G

Variant summary

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

The NM_000103.4(CYP19A1):​c.629-16T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 1,603,584 control chromosomes in the GnomAD database, including 200,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14761 hom., cov: 32)
  • Exomes 𝑓: 0.50 (185522 hom.)
• Consequence: CYP19A1 NM_000103.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.29

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=-0.73).
• BP6: Variant 15-51218671-A-C is Benign according to our data. Variant chr15-51218671-A-C is described in ClinVar as [Benign]. Clinvar id is 1174721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51218671-A-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CYP19A1	NM_000103.4	c.629-16T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000396402.6
MIR4713HG	NR_146310.1	n.195-59312A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP19A1	ENST00000396402.6	c.629-16T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000103.4	P1
MIR4713HG	ENST00000559909.1	n.195-59312A>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64466 AN: 151910 Hom.: 14762 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.446

GnomAD3 exomes AF: 0.453 AC: 106346 AN: 234652 Hom.: 25033 AF XY: 0.459 AC XY: 58124 AN XY: 126764

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.518

Gnomad SAS exome AF: 0.357

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.500 AC: 726445 AN: 1451556 Hom.: 185522 Cov.: 62 AF XY: 0.498 AC XY: 359067 AN XY: 721224

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.531

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.424 AC: 64486 AN: 152028 Hom.: 14761 Cov.: 32 AF XY: 0.420 AC XY: 31242 AN XY: 74324

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.540

Gnomad4 EAS AF: 0.497

Gnomad4 SAS AF: 0.362

Gnomad4 FIN AF: 0.494

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.444

Alfa AF: 0.483 Hom.: 3795

Bravo AF: 0.410

Asia WGS AF: 0.381 AC: 1327 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.0
DANN	Benign	0.87

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: rs4324076; hg19: chr15-51510868; COSMIC: COSV53058038; COSMIC: COSV53058038;