Variant 11-101127596-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000926.4(PGR):c.1475G>T(p.Arg492Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,304,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PGR
NM_000926.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4 linkuse as main transcript	c.1475G>T	p.Arg492Leu	missense_variant	1/8	ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10 linkuse as main transcript	c.1475G>T	p.Arg492Leu	missense_variant	1/8	1	NM_000926.4	P1	P06401-1

Frequencies

GnomAD3 genomes

AF:

0.0000792

AC:

AN:

151462

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:

0.00216

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1153094

Hom.:

Cov.:

AF XY:

0.0000216

AC XY:

AN XY:

555736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000742

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000213

GnomAD4 genome

AF:

0.0000792

AC:

AN:

151570

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74090

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00217

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000117

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000291

AC:

AN:

3452

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.1475G>T (p.R492L) alteration is located in exon 1 (coding exon 1) of the PGR gene. This alteration results from a G to T substitution at nucleotide position 1475, causing the arginine (R) at amino acid position 492 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.49

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;.;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.8

N;N;.;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.0020

D;D;.;.

Sift4G

Benign

0.43

T;T;T;T

Polyphen

1.0

D;.;.;.

Vest4

0.41

MutPred

0.62

Loss of methylation at R492 (P = 0.1624);Loss of methylation at R492 (P = 0.1624);Loss of methylation at R492 (P = 0.1624);Loss of methylation at R492 (P = 0.1624);

MVP

0.58

ClinPred

0.87

GERP RS

3.1

Varity_R

0.22

gMVP

0.44

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