rs371232368
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_001083116.3(PRF1):c.1207A>G(p.Thr403Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,212 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 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PRF1
NM_001083116.3 missense
NM_001083116.3 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 1.34
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 Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001083116.3
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.1909191).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.1207A>G | p.Thr403Ala | missense_variant | 3/3 | ENST00000441259.2 | |
PRF1 | NM_005041.6 | c.1207A>G | p.Thr403Ala | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.1207A>G | p.Thr403Ala | missense_variant | 3/3 | 5 | NM_001083116.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 151920Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248464Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134984
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461174Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726894
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GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152038Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74314
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 07, 2022 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 403 of the PRF1 protein (p.Thr403Ala). This variant is present in population databases (rs371232368, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PRF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 536219). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
MPC
0.18
ClinPred
T
GERP RS
Varity_R
gMVP
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