rs202091142

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001083116.3(PRF1):ā€‹c.380A>Gā€‹(p.Asn127Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

PRF1
NM_001083116.3 missense

Scores

4
12
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.13
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRF1NM_001083116.3 linkuse as main transcriptc.380A>G p.Asn127Ser missense_variant 2/3 ENST00000441259.2 NP_001076585.1 P14222
PRF1NM_005041.6 linkuse as main transcriptc.380A>G p.Asn127Ser missense_variant 2/3 NP_005032.2 P14222

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRF1ENST00000441259.2 linkuse as main transcriptc.380A>G p.Asn127Ser missense_variant 2/35 NM_001083116.3 ENSP00000398568.1 P14222

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461746
Hom.:
0
Cov.:
34
AF XY:
0.00000413
AC XY:
3
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 09, 2023Variant summary: PRF1 c.380A>G (p.Asn127Ser) results in a conservative amino acid change located in the membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250712 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.380A>G has been reported in the literature in an individual affected with adult onset Hemophagocytic Lymphohistiocytosis (example: Jin_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29357941, 32375849). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial hemophagocytic lymphohistiocytosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 14, 2022This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 127 of the PRF1 protein (p.Asn127Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adult onset hemophagocytic lymphohistiocytosis (PMID: 29357941). 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: 572802). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Uncertain
0.022
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
.;D;D
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.83
T;.;T
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.71
D;D;D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Pathogenic
3.3
.;M;M
PrimateAI
Uncertain
0.48
T
PROVEAN
Uncertain
-3.7
.;D;D
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
.;D;D
Polyphen
1.0
.;D;D
Vest4
0.65, 0.65
MutPred
0.60
Loss of stability (P = 0.0345);Loss of stability (P = 0.0345);Loss of stability (P = 0.0345);
MVP
0.94
MPC
0.34
ClinPred
0.93
D
GERP RS
5.7
Varity_R
0.53
gMVP
0.52

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: rs202091142; hg19: chr10-72360279; API