rs2236722

chr15-51242798-A-Gchr15-51242798-A-T

Variant summary

Our verdict is Benign. Variant got -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 same amino acid change has been previously reported as Likely benignin 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

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

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 316479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-51242798-A-G is described in Lovd as [Benign]. Variant chr15-51242798-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP19A1	NM_000103.4	c.115T>C	p.Trp39Arg	missense_variant	2/10	ENST00000396402.6
MIR4713HG	NR_146310.1	n.195-35185A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP19A1	ENST00000396402.6	c.115T>C	p.Trp39Arg	missense_variant	2/10	1	NM_000103.4	P1
MIR4713HG	ENST00000559909.1	n.195-35185A>G		intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes AF: 0.00336 AC: 845 AN: 251274 Hom.: 17 AF XY: 0.00311 AC XY: 422 AN XY: 135800

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 SAS exome AF: 0.000131

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0393

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.00194

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0353

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000964 Hom.: 4

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	This variant is associated with the following publications: (PMID: 10956405, 20133979, 16322257) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Aromatase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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;D;D;.;T;.;.;.;T;T;T
Eigen	Benign	0.10
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0069	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M;M;M;.;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.033	D;D;D;T;D;D;D;D;D;D;D
Sift4G	Uncertain	0.055	T;T;T;T;.;T;T;T;T;T;.
Polyphen		0.34	B;B;B;.;.;.;.;.;.;.;.
Vest4		0.35
MutPred		0.27		Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);Loss of catalytic residue at L37 (P = 0.0025);
MVP		0.96
MPC		0.23
ClinPred		0.071	T
GERP RS		5.5
Varity_R		0.70
gMVP		0.90

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: rs2236722; hg19: chr15-51534995;