11-101126126-T-C
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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
NM_001271162.2 5_prime_UTR_premature_start_codon_gain
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 3.40
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]
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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 |
---|---|---|---|---|---|---|---|---|
PGR | NM_000926.4 | c.1670A>G | p.Tyr557Cys | missense_variant | 2/8 | ENST00000325455.10 | NP_000917.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PGR | ENST00000325455.10 | c.1670A>G | p.Tyr557Cys | missense_variant | 2/8 | 1 | NM_000926.4 | ENSP00000325120.5 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251442Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135902
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32AN XY: 727214
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74472
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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 | Mar 25, 2024 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
M;M;.;.;.
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D;.;.;.
REVEL
Benign
Sift
Uncertain
D;D;.;.;.
Sift4G
Uncertain
D;D;D;D;.
Polyphen
P;.;.;.;.
Vest4
MutPred
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
ClinPred
D
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at