rs4646

Positions:

• chr15-51210647-A-C
• chr15-51210647-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.*161T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 752,108 control chromosomes in the GnomAD database, including 187,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37731 hom., cov: 32)
  • Exomes 𝑓: 0.70 (149410 hom.)
• Consequence: CYP19A1 NM_000103.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.27

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=-0.93).
• BP6: Variant 15-51210647-A-C is Benign according to our data. Variant chr15-51210647-A-C is described in ClinVar as [Benign]. Clinvar id is 316467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51210647-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.*161T>G		3_prime_UTR_variant	10/10	ENST00000396402.6	NP_000094.2
MIR4713HG	NR_146310.1	n.195-67336A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.*161T>G		3_prime_UTR_variant	10/10	1	NM_000103.4	ENSP00000379683	P1
CYP19A1	ENST00000559878.5	c.*161T>G		3_prime_UTR_variant	9/9	1		ENSP00000453149	P1
MIR4713HG	ENST00000559909.1	n.195-67336A>C		intron_variant, non_coding_transcript_variant		4
CYP19A1	ENST00000396404.8	c.*161T>G		3_prime_UTR_variant	11/11	2		ENSP00000379685	P1

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106604 AN: 151928 Hom.: 37705 Cov.: 32

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.672 AC: 147573 AN: 219628 Hom.: 50443 AF XY: 0.679 AC XY: 81398 AN XY: 119940

Gnomad AFR exome AF: 0.695

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.749

Gnomad EAS exome AF: 0.674

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.716

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.701

GnomAD4 exome AF: 0.701 AC: 420906 AN: 600062 Hom.: 149410 Cov.: 4 AF XY: 0.702 AC XY: 230169 AN XY: 327918

Gnomad4 AFR exome AF: 0.685

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.754

Gnomad4 EAS exome AF: 0.707

Gnomad4 SAS exome AF: 0.627

Gnomad4 FIN exome AF: 0.720

Gnomad4 NFE exome AF: 0.735

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.702 AC: 106677 AN: 152046 Hom.: 37731 Cov.: 32 AF XY: 0.698 AC XY: 51840 AN XY: 74298

Gnomad4 AFR AF: 0.693

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.625

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.738

Gnomad4 OTH AF: 0.682

Alfa AF: 0.726 Hom.: 73977

Bravo AF: 0.688

Asia WGS AF: 0.639 AC: 2224 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aromatase deficiency Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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: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	-0.93
CADD	Benign	0.10
DANN	Benign	0.46

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: rs4646; hg19: chr15-51502844; COSMIC: COSV53058004; COSMIC: COSV53058004;