rs578092914
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001083116.3(PRF1):c.133G>A(p.Gly45Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000807 in 1,611,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
PRF1
NM_001083116.3 missense
NM_001083116.3 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 6.93
Genes affected
PRF1 (HGNC:9360): (perforin 1) This gene encodes a protein with structural similarities to complement component C9 that is important in immunity. This protein forms membrane pores that allow the release of granzymes and subsequent cytolysis of target cells. Whether pore formation occurs in the plasma membrane of target cells or in an endosomal membrane inside target cells is subject to debate. Mutations in this gene are associated with a variety of human disease including diabetes, multiple sclerosis, lymphomas, autoimmune lymphoproliferative syndrome (ALPS), aplastic anemia, and familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a rare and lethal autosomal recessive disorder of early childhood. [provided by RefSeq, Aug 2017]
PALD1 (HGNC:23530): (phosphatase domain containing paladin 1) Predicted to enable protein tyrosine phosphatase activity. Predicted to be involved in peptidyl-tyrosine dephosphorylation. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 10-70600770-C-T is Pathogenic according to our data. Variant chr10-70600770-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 468300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.133G>A | p.Gly45Arg | missense_variant | 2/3 | ENST00000441259.2 | NP_001076585.1 | |
PRF1 | NM_005041.6 | c.133G>A | p.Gly45Arg | missense_variant | 2/3 | NP_005032.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.133G>A | p.Gly45Arg | missense_variant | 2/3 | 5 | NM_001083116.3 | ENSP00000398568 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 246994Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133872
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GnomAD4 exome AF: 0.00000823 AC: 12AN: 1458928Hom.: 0 Cov.: 34 AF XY: 0.00000689 AC XY: 5AN XY: 725406
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GnomAD4 genome AF: 0.00000656 AC: 1AN: 152362Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74506
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
PRF1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 20, 2024 | The PRF1 c.133G>A variant is predicted to result in the amino acid substitution p.Gly45Arg. This variant has been reported in the homozygous or compound heterozygous state in three individuals with haemophagocytic lymphohistiocytosis (HLH) (Gadoury-Levesque et al. 2020. PubMed ID: 32542393; Kogawa et al. 2002. PubMed ID: 11756153; Internal Data; PreventionGenetics). In vitro functional studies demonstrate partial proteolytic maturation and reduced perforin activity (Risma et al. 2006. PubMed ID: 16374518). This variant is reported in 0.0099% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 45 of the PRF1 protein (p.Gly45Arg). This variant is present in population databases (rs578092914, gnomAD 0.01%). This missense change has been observed in individual(s) with PRF1-related disorders (PMID: 11756153, 29357941, 30697212; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 468300). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRF1 protein function. This variant disrupts the p.Gly45 amino acid residue in PRF1. Other variant(s) that disrupt this residue have been observed in individuals with PRF1-related conditions (PMID: 14757862), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;.;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;D
Sift4G
Pathogenic
.;D;D
Polyphen
1.0
.;D;D
Vest4
0.97, 0.96
MutPred
Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);
MVP
0.95
MPC
0.59
ClinPred
D
GERP RS
Varity_R
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Splicing
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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