11-101126126-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001271162.2(PGR):​c.-113A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

PGR
NM_001271162.2 5_prime_UTR_premature_start_codon_gain

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40
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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20522669).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PGRNM_000926.4 linkuse as main transcriptc.1670A>G p.Tyr557Cys missense_variant 2/8 ENST00000325455.10 NP_000917.3 P06401-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PGRENST00000325455.10 linkuse as main transcriptc.1670A>G p.Tyr557Cys missense_variant 2/81 NM_000926.4 ENSP00000325120.5 P06401-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152192
Hom.:
0
Cov.:
33
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:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251442
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1461820
Hom.:
0
Cov.:
31
AF XY:
0.0000440
AC XY:
32
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000499
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152310
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4

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 GeneticsMar 25, 2024The c.1670A>G (p.Y557C) alteration is located in exon 2 (coding exon 2) of the PGR gene. This alteration results from a A to G substitution at nucleotide position 1670, causing the tyrosine (Y) at amino acid position 557 to be replaced by a cysteine (C). 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
0.64
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;.;T;.;T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Benign
0.72
D
LIST_S2
Uncertain
0.91
D;D;D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.21
T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
2.0
M;M;.;.;.
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-4.4
D;D;.;.;.
REVEL
Benign
0.20
Sift
Uncertain
0.0010
D;D;.;.;.
Sift4G
Uncertain
0.014
D;D;D;D;.
Polyphen
0.72
P;.;.;.;.
Vest4
0.50
MutPred
0.56
Loss of phosphorylation at Y557 (P = 0.0564);Loss of phosphorylation at Y557 (P = 0.0564);Loss of phosphorylation at Y557 (P = 0.0564);Loss of phosphorylation at Y557 (P = 0.0564);.;
MVP
0.66
ClinPred
0.77
D
GERP RS
5.5
Varity_R
0.32
gMVP
0.48

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.

Other links and lift over

dbSNP: rs571702063; hg19: chr11-100996857; API