NM_000103.4:c.858+118A>C

Variant names:

• chr15-51215585-T-G
• rs2289106
• NM_000103.4:c.858+118A>C

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.858+118A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,575,414 control chromosomes in the GnomAD database, including 200,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15020 hom., cov: 32)
  • Exomes 𝑓: 0.51 (185781 hom.)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.739
• Publications: 5 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=-0.86).
• BP6: Variant 15-51215585-T-G is Benign according to our data. Variant chr15-51215585-T-G is described in ClinVar as Benign. ClinVar VariationId is 1279539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000103.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	NM_000103.4	MANE Select	c.858+118A>C		intron	N/A	NP_000094.2
	CYP19A1	NM_001347248.1		c.858+118A>C		intron	N/A	NP_001334177.1
	CYP19A1	NM_001347249.2		c.858+118A>C		intron	N/A	NP_001334178.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.858+118A>C		intron	N/A	ENSP00000379683.1
	CYP19A1	ENST00000559878.5	TSL:1	c.858+118A>C		intron	N/A	ENSP00000453149.1
	CYP19A1	ENST00000439712.6	TSL:1	n.858+118A>C		intron	N/A	ENSP00000390614.2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64745 AN: 151766 Hom.: 15021 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.450

GnomAD4 exome AF: 0.506 AC: 720329 AN: 1423530 Hom.: 185781 AF XY: 0.504 AC XY: 355690 AN XY: 705958

African (AFR) AF: 0.220 AC: 7137 AN: 32504

American (AMR) AF: 0.333 AC: 13318 AN: 39950

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14297 AN: 25648

East Asian (EAS) AF: 0.479 AC: 18187 AN: 38000

South Asian (SAS) AF: 0.388 AC: 31985 AN: 82478

European-Finnish (FIN) AF: 0.528 AC: 24233 AN: 45918

Middle Eastern (MID) AF: 0.433 AC: 2472 AN: 5706

European-Non Finnish (NFE) AF: 0.530 AC: 579827 AN: 1094214

Other (OTH) AF: 0.488 AC: 28873 AN: 59112

GnomAD4 genome AF: 0.426 AC: 64758 AN: 151884 Hom.: 15020 Cov.: 32 AF XY: 0.425 AC XY: 31519 AN XY: 74218

African (AFR) AF: 0.233 AC: 9669 AN: 41500

American (AMR) AF: 0.372 AC: 5682 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1961 AN: 3468

East Asian (EAS) AF: 0.510 AC: 2594 AN: 5084

South Asian (SAS) AF: 0.397 AC: 1896 AN: 4770

European-Finnish (FIN) AF: 0.525 AC: 5531 AN: 10542

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35875 AN: 67938

Other (OTH) AF: 0.448 AC: 946 AN: 2112

Alfa AF: 0.353 Hom.: 1117

Bravo AF: 0.409

Asia WGS AF: 0.387 AC: 1347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.50
DANN	Benign	0.74
PhyloP100		-0.74
PromoterAI		-0.015	Neutral
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: rs2289106; hg19: chr15-51507782; COSMIC: COSV53058033; COSMIC: COSV53058033;