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
• Publications: 170 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=-0.93).
• BP6: Variant 15-51210647-A-C is Benign according to our data. Variant chr15-51210647-A-C is described in ClinVar as Benign. ClinVar VariationId is 316467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.733 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	ENST00000396402.6	c.*161T>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_000103.4	ENSP00000379683.1

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

African (AFR) AF: 0.685 AC: 11795 AN: 17214

American (AMR) AF: 0.496 AC: 20764 AN: 41872

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 15579 AN: 20656

East Asian (EAS) AF: 0.707 AC: 24790 AN: 35052

South Asian (SAS) AF: 0.627 AC: 42571 AN: 67900

European-Finnish (FIN) AF: 0.720 AC: 28721 AN: 39914

Middle Eastern (MID) AF: 0.726 AC: 2974 AN: 4094

European-Non Finnish (NFE) AF: 0.735 AC: 250921 AN: 341184

Other (OTH) 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

African (AFR) AF: 0.693 AC: 28710 AN: 41452

American (AMR) AF: 0.570 AC: 8700 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2667 AN: 3468

East Asian (EAS) AF: 0.682 AC: 3525 AN: 5168

South Asian (SAS) AF: 0.625 AC: 3013 AN: 4820

European-Finnish (FIN) AF: 0.720 AC: 7616 AN: 10580

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.738 AC: 50193 AN: 67970

Other (OTH) AF: 0.682 AC: 1443 AN: 2116

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

Dec 06, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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
PhyloP100		-2.3
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: rs4646; hg19: chr15-51502844; COSMIC: COSV53058004; COSMIC: COSV53058004;