rs2236722

Variant names:

• chr15-51242798-A-G
• rs2236722
• NM_000103.4:c.115T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-51242798-A-G
• chr15-51242798-A-T
• chr15-51242798-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000103.4(CYP19A1):​c.115T>C​(p.Trp39Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,582,966 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: CYP19A1 NM_000103.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.40
• Publications: 54 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 (MetaRNN=0.006927401).
• BP6: Variant 15-51242798-A-G is Benign according to our data. Variant chr15-51242798-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 316479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00127 (194/152288) while in subpopulation EAS AF = 0.0353 (183/5180). AF 95% confidence interval is 0.0311. There are 3 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	NM_000103.4	MANE Select	c.115T>C	p.Trp39Arg	missense	Exon 2 of 10	NP_000094.2
	CYP19A1	NM_001347248.1		c.115T>C	p.Trp39Arg	missense	Exon 2 of 10	NP_001334177.1	P11511-1
	CYP19A1	NM_001347249.2		c.115T>C	p.Trp39Arg	missense	Exon 2 of 10	NP_001334178.1	P11511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.115T>C	p.Trp39Arg	missense	Exon 2 of 10	ENSP00000379683.1	P11511-1
	CYP19A1	ENST00000559878.5	TSL:1	c.115T>C	p.Trp39Arg	missense	Exon 1 of 9	ENSP00000453149.1	P11511-1
	CYP19A1	ENST00000405913.7	TSL:1	c.115T>C	p.Trp39Arg	missense	Exon 1 of 4	ENSP00000383930.3	P11511-2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00336 AC: 845 AN: 251274 AF XY: 0.00311

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0452

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00118 AC: 1683 AN: 1430678 Hom.: 36 Cov.: 25 AF XY: 0.00116 AC XY: 830 AN XY: 713870

African (AFR) AF: 0.00 AC: 0 AN: 32800

American (AMR) AF: 0.0000447 AC: 2 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.0393 AC: 1554 AN: 39556

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1083604

Other (OTH) AF: 0.00194 AC: 115 AN: 59356

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0353 AC: 183 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00107 Hom.: 8

Bravo AF: 0.00175

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00327 AC: 397

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aromatase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.0037	T
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.10
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.36
Sift	Benign	0.033	D
Sift4G	Uncertain	0.055	T
Polyphen		0.34	B
Vest4		0.35
MutPred		0.27		Loss of catalytic residue at L37 (P = 0.0025)
MVP		0.96
MPC		0.23
ClinPred		0.071	T
GERP RS		5.5
PromoterAI		0.036	Neutral
Varity_R		0.70
gMVP		0.90
Mutation Taster		=97/3	polymorphism

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: rs2236722; hg19: chr15-51534995;