rs138126912
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_001083116.3(PRF1):c.1310C>T(p.Ala437Val) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,614,020 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00074 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 3 hom. )
Consequence
PRF1
NM_001083116.3 missense
NM_001083116.3 missense
Scores
2
11
5
Clinical Significance
Conservation
PhyloP100: 3.63
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 Likely_benign. Variant got -2 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001083116.3
BS2
?
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.1310C>T | p.Ala437Val | missense_variant | 3/3 | ENST00000441259.2 | |
PRF1 | NM_005041.6 | c.1310C>T | p.Ala437Val | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.1310C>T | p.Ala437Val | missense_variant | 3/3 | 5 | NM_001083116.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000736 AC: 112AN: 152172Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000730 AC: 183AN: 250636Hom.: 0 AF XY: 0.000708 AC XY: 96AN XY: 135616
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GnomAD4 exome AF: 0.00112 AC: 1631AN: 1461730Hom.: 3 Cov.: 33 AF XY: 0.00108 AC XY: 785AN XY: 727170
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GnomAD4 genome ? AF: 0.000735 AC: 112AN: 152290Hom.: 1 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74456
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 21, 2017 | The PRF1 c.1310C>T (p.Ala437Val) missense variant has been reported in five studies in which it was found in a total of six individuals with familial hemophagocytic lymphohistocytosis including in a compound heterozygous state with another missense variant in two individuals and in a heterozygous state where a second variant was not detected in four individuals including one sib-pair. The variant was also found in a heterozygous state in the unaffected father of the sib-pair (Zhang et al. 2011; Zhang et al. 2014; Willig et al. 2015; Džoljić et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Ala437Val variant results in absent NK-cell function and 61% of normal perforin levels (Zhang et al. 2011). Based on the evidence, the p.Ala437Val variant is classified as likely pathogenic for familial hemophagocytic lymphohistocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 21, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 437 of the PRF1 protein (p.Ala437Val). This variant is present in population databases (rs138126912, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with suspected familial hemophagocytic lymphohistiocytosis (HLH), atypical HLH, and/or lymphoma of the brain (PMID: 21881043, 25845254, 25937001, 29263817). ClinVar contains an entry for this variant (Variation ID: 300327). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 25, 2022 | Variant summary: PRF1 c.1310C>T (p.Ala437Val) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 250636 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00073 vs 0.0027), allowing no conclusion about variant significance. c.1310C>T has been reported in the literature as a non-informative genotype (second allele not specified) or in a proposed model of synergistic heterozygosity with a heterozygous variant in a different gene in individuals affected with features of Familial Hemophagocytic Lymphohistiocytosis (FHL)/Primary Lymphoma with a family history of FHL/Omphalocele and Liver failure (example, Zhang_2011, Dolji_2015, Noll_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2022 | The c.1310C>T (p.A437V) alteration is located in exon 3 (coding exon 2) of the PRF1 gene. This alteration results from a C to T substitution at nucleotide position 1310, causing the alanine (A) at amino acid position 437 to be replaced by a valine (V). The p.A437V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.53
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at