Genetic Variant NM_000926.4:c.1459G>C (chr11-101127612-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000926.4(PGR):c.1459G>C(p.Gly487Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,152,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. G487S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PGR
NM_000926.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.121

Publications

0 publications found

Variant links:

Genes affected

PGR (HGNC:8910): (progesterone receptor) This gene encodes a member of the steroid receptor superfamily. The encoded protein mediates the physiological effects of progesterone, which plays a central role in reproductive events associated with the establishment and maintenance of pregnancy. This gene uses two distinct promotors and translation start sites in the first exon to produce several transcript variants, both protein coding and non-protein coding. Two of the isoforms (A and B) are identical except for an additional 165 amino acids found in the N-terminus of isoform B and mediate their own response genes and physiologic effects with little overlap. [provided by RefSeq, Sep 2015]

PGR links:

PGR-AS1 (HGNC:52650): (PGR antisense RNA 1)

PGR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.19741365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4 link	c.1459G>C	p.Gly487Arg	missense_variant	Exon 1 of 8	ENST00000325455.10	NP_000917.3	P06401-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGR	ENST00000325455.10 link	c.1459G>C	p.Gly487Arg	missense_variant	Exon 1 of 8	1	NM_000926.4	ENSP00000325120.5		P06401-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000260

AC:

AN:

1152890

Hom.:

Cov.:

AF XY:

0.00000540

AC XY:

AN XY:

555348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23220

American (AMR)

AF:

0.00

AC:

AN:

9042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15450

East Asian (EAS)

AF:

0.00

AC:

AN:

27022

South Asian (SAS)

AF:

0.0000291

AC:

AN:

34312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3886

European-Non Finnish (NFE)

AF:

0.00000207

AC:

AN:

968016

Other (OTH)

AF:

0.00

AC:

AN:

46966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000660

AC:

AN:

151444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67806

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.081

T;.;T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;N;.;.

PhyloP100

-0.12

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.94

N;N;.;.

REVEL

Benign

0.048

Sift

Uncertain

0.0020

D;D;.;.

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.55

P;.;.;.

Vest4

0.12

MutPred

0.59

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);

MVP

0.15

ClinPred

0.52

GERP RS

1.8

Varity_R

0.16

gMVP

0.29

Mutation Taster

=96/4

polymorphism

(source)

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

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NM_000926.4:c.1459G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over