rs578092914

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

Scores

14
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.93
Variant links:
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]

Genome browser will be placed here

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
PRF1NM_001083116.3 linkuse as main transcriptc.133G>A p.Gly45Arg missense_variant 2/3 ENST00000441259.2 NP_001076585.1
PRF1NM_005041.6 linkuse as main transcriptc.133G>A p.Gly45Arg missense_variant 2/3 NP_005032.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRF1ENST00000441259.2 linkuse as main transcriptc.133G>A p.Gly45Arg missense_variant 2/35 NM_001083116.3 ENSP00000398568 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152244
Hom.:
0
Cov.:
32
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:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
246994
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
133872
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:
0.0000990
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000823
AC:
12
AN:
1458928
Hom.:
0
Cov.:
34
AF XY:
0.00000689
AC XY:
5
AN XY:
725406
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000465
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152362
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 submitterclinical testingBaylor GeneticsMar 21, 2024- -
PRF1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 20, 2024The 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 submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundMay 27, 2022- -
Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
.;D;D
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.85
D;.;T
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.4
.;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-7.7
.;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
.;D;D
Polyphen
1.0
.;D;D
Vest4
0.97, 0.96
MutPred
0.97
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
0.99
D
GERP RS
4.8
Varity_R
0.84
gMVP
0.98

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: rs578092914; hg19: chr10-72360526; COSMIC: COSV100942502; API