chr11-101039138-G-T

Variant summary

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

The NM_000926.4(PGR):​c.2780C>A​(p.Pro927His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,611,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PGR
NM_000926.4 missense

Scores

9
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PGRNM_000926.4 linkuse as main transcriptc.2780C>A p.Pro927His missense_variant 8/8 ENST00000325455.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PGRENST00000325455.10 linkuse as main transcriptc.2780C>A p.Pro927His missense_variant 8/81 NM_000926.4 P1P06401-1

Frequencies

GnomAD3 genomes
AF:
0.000132
AC:
20
AN:
151682
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000329
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:
0.000177
Gnomad OTH
AF:
0.000960
GnomAD3 exomes
AF:
0.0000957
AC:
24
AN:
250742
Hom.:
0
AF XY:
0.0000959
AC XY:
13
AN XY:
135544
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000103
AC:
151
AN:
1459610
Hom.:
0
Cov.:
30
AF XY:
0.000102
AC XY:
74
AN XY:
726192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000247
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000113
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000132
AC:
20
AN:
151682
Hom.:
0
Cov.:
32
AF XY:
0.0000540
AC XY:
4
AN XY:
74088
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000329
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.000960
Alfa
AF:
0.0000451
Hom.:
0
Bravo
AF:
0.000102
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.000273
EpiControl
AF:
0.000178

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 submitterclinical testingAmbry GeneticsSep 26, 2022The c.2780C>A (p.P927H) alteration is located in exon 8 (coding exon 8) of the PGR gene. This alteration results from a C to A substitution at nucleotide position 2780, causing the proline (P) at amino acid position 927 to be replaced by a histidine (H). 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
Pathogenic
0.83
BayesDel_addAF
Uncertain
0.058
T
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.80
T;T;T
M_CAP
Pathogenic
0.55
D
MetaRNN
Uncertain
0.45
T;T;T
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Uncertain
2.5
M;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.2
D;D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
0.79
P;.;.
Vest4
0.28
MutPred
0.55
Gain of MoRF binding (P = 0.0517);.;.;
MVP
0.90
ClinPred
0.77
D
GERP RS
4.8
Varity_R
0.86
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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.

Other links and lift over

dbSNP: rs769064153; hg19: chr11-100909869; API