11-101127564-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000926.4(PGR):​c.1507G>A​(p.Ala503Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 151,534 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000016 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PGR
NM_000926.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0830

Publications

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15797713).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PGRNM_000926.4 linkc.1507G>A p.Ala503Thr 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
PGRENST00000325455.10 linkc.1507G>A p.Ala503Thr missense_variant Exon 1 of 8 1 NM_000926.4 ENSP00000325120.5 P06401-1

Frequencies

GnomAD3 genomes
AF:
0.0000396
AC:
6
AN:
151534
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000164
AC:
2
AN:
1221690
Hom.:
0
Cov.:
30
AF XY:
0.00000168
AC XY:
1
AN XY:
596962
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000393
AC:
1
AN:
25438
American (AMR)
AF:
0.00
AC:
0
AN:
19528
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19608
East Asian (EAS)
AF:
0.00
AC:
0
AN:
27340
South Asian (SAS)
AF:
0.00
AC:
0
AN:
51916
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
29824
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3876
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
994612
Other (OTH)
AF:
0.0000202
AC:
1
AN:
49548
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000396
AC:
6
AN:
151534
Hom.:
0
Cov.:
33
AF XY:
0.0000405
AC XY:
3
AN XY:
74010
show subpopulations
African (AFR)
AF:
0.000145
AC:
6
AN:
41302
American (AMR)
AF:
0.00
AC:
0
AN:
15222
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3462
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5104
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10492
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
308
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67826
Other (OTH)
AF:
0.00
AC:
0
AN:
2080
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.517
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000529

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.1507G>A (p.A503T) alteration is located in exon 1 (coding exon 1) of the PGR gene. This alteration results from a G to A substitution at nucleotide position 1507, causing the alanine (A) at amino acid position 503 to be replaced by a threonine (T). 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
0.092
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
12
DANN
Uncertain
0.99
DEOGEN2
Benign
0.066
T;.;T;.
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.53
T;T;T;T
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.16
T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.76
N;N;.;.
PhyloP100
-0.083
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
0.18
N;N;.;.
REVEL
Benign
0.036
Sift
Benign
0.23
T;T;.;.
Sift4G
Benign
0.31
T;T;T;T
Polyphen
0.035
B;.;.;.
Vest4
0.16
MutPred
0.50
Gain of glycosylation at A503 (P = 0.0032);Gain of glycosylation at A503 (P = 0.0032);Gain of glycosylation at A503 (P = 0.0032);Gain of glycosylation at A503 (P = 0.0032);
MVP
0.52
ClinPred
0.48
T
GERP RS
-0.27
PromoterAI
-0.083
Neutral
Varity_R
0.043
gMVP
0.32
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs1034768032; hg19: chr11-100998295; API