Genetic Variant PGR:p.Ala500Asp (chr11-101127572-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000926.4(PGR):c.1499C>A(p.Ala500Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PGR
NM_000926.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4 link	c.1499C>A	p.Ala500Asp	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.1499C>A	p.Ala500Asp	missense_variant	Exon 1 of 8	1	NM_000926.4	ENSP00000325120.5		P06401-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1218864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

595134

African (AFR)

AF:

0.00

AC:

AN:

25306

American (AMR)

AF:

0.00

AC:

AN:

18828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19208

East Asian (EAS)

AF:

0.00

AC:

AN:

27304

South Asian (SAS)

AF:

0.00

AC:

AN:

50832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3886

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

994822

Other (OTH)

AF:

0.00

AC:

AN:

49516

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1499C>A (p.A500D) alteration is located in exon 1 (coding exon 1) of the PGR gene. This alteration results from a C to A substitution at nucleotide position 1499, causing the alanine (A) at amino acid position 500 to be replaced by an aspartic acid (D). 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

2.0

M;M;.;.

PhyloP100

2.2

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.42

N;N;.;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.020

D;D;.;.

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.053

B;.;.;.

Vest4

0.50

MutPred

0.47

Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);

MVP

0.80

ClinPred

0.46

GERP RS

1.9

PromoterAI

-0.086

Neutral

(source)

Varity_R

0.26

gMVP

0.41

Mutation Taster

=86/14

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over