rs2236722

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.40

Variant links:

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]

CYP19A1 links:

MIR4713HG (HGNC:53124): (MIR4713 host gene)

MIR4713HG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP19A1	NM_000103.4 linkuse as main transcript	c.115T>C	p.Trp39Arg	missense_variant	2/10	ENST00000396402.6
MIR4713HG	NR_146310.1 linkuse as main transcript	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 linkuse as main transcript	c.115T>C	p.Trp39Arg	missense_variant	2/10	1	NM_000103.4	P1	P11511-1
MIR4713HG	ENST00000559909.1 linkuse as main transcript	n.195-35185A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152170

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00311

AC XY:

422

AN XY:

135800

show subpopulations

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.:

Cov.:

AF XY:

0.00116

AC XY:

830

AN XY:

713870

show subpopulations

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.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74464

show subpopulations

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.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00327

AC:

397

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

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

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

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

LIST_S2

Benign

0.63

.;.;T;T;T;T;.;T;T;T;T

MetaRNN

Benign

0.0069

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.2

M;M;M;.;.;.;M;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.53

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over