15-51222375-G-C

Variant names:

• chr15-51222375-G-C
• rs28757184
• NM_000103.4:c.602C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000103.4(CYP19A1):​c.602C>G​(p.Thr201Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T201M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP19A1 NM_000103.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070343345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP19A1	NM_000103.4	c.602C>G	p.Thr201Arg	missense_variant	Exon 5 of 10	ENST00000396402.6	NP_000094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP19A1	ENST00000396402.6	c.602C>G	p.Thr201Arg	missense_variant	Exon 5 of 10	1	NM_000103.4	ENSP00000379683.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.0040
DANN	Benign	0.72
DEOGEN2	Benign	0.20	T;T;T;T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.58	.;.;T;T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.070	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.52	N;N;N;.;.;N;N
PhyloP100		-0.077
PrimateAI	Benign	0.19	T
PROVEAN	Benign	2.7	N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;.;T;T;T
Polyphen		0.0	B;B;B;.;.;.;.
Vest4		0.18
MutPred		0.53		Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);
MVP		0.42
MPC		0.14
ClinPred		0.042	T
GERP RS		-3.7
Varity_R		0.081
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28757184; hg19: chr15-51514572;