rs4646

Variant names:

• chr15-51210647-A-C
• rs4646
• NM_000103.4:c.*161T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-51210647-A-C
• chr15-51210647-A-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.*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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.*161T>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000396402.6	NP_000094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402	c.*161T>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_000103.4	ENSP00000379683.1
CYP19A1	ENST00000559878	c.*161T>G		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000453149.1
CYP19A1	ENST00000396404	c.*161T>G		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000379685.4
MIR4713HG	ENST00000559909.1	n.195-67336A>C		intron_variant	Intron 1 of 2	4

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

GnomAD2 exomes AF: 0.672 AC: 147573 AN: 219628 AF XY: 0.679

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 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 AC: 11795 AN: 17214

Gnomad4 AMR exome AF: 0.496 AC: 20764 AN: 41872

Gnomad4 ASJ exome AF: 0.754 AC: 15579 AN: 20656

Gnomad4 EAS exome AF: 0.707 AC: 24790 AN: 35052

Gnomad4 SAS exome AF: 0.627 AC: 42571 AN: 67900

Gnomad4 FIN exome AF: 0.720 AC: 28721 AN: 39914

Gnomad4 NFE exome AF: 0.735 AC: 250921 AN: 341184

Gnomad4 Remaining exome AF: 0.708 AC: 22791 AN: 32176

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 AC: 0.692608 AN: 0.692608

Gnomad4 AMR AF: 0.570 AC: 0.569894 AN: 0.569894

Gnomad4 ASJ AF: 0.769 AC: 0.769031 AN: 0.769031

Gnomad4 EAS AF: 0.682 AC: 0.682082 AN: 0.682082

Gnomad4 SAS AF: 0.625 AC: 0.625104 AN: 0.625104

Gnomad4 FIN AF: 0.720 AC: 0.719849 AN: 0.719849

Gnomad4 NFE AF: 0.738 AC: 0.738458 AN: 0.738458

Gnomad4 OTH AF: 0.682 AC: 0.681947 AN: 0.681947

Alfa AF: 0.722 Hom.: 167351

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 06, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.10
DANN	Benign	0.46
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

Publications

LitVar

Other links and lift over

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