rs35418374

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001083116.3(PRF1):​c.11G>T​(p.Arg4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,437,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PRF1
NM_001083116.3 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.04
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.123137504).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRF1NM_001083116.3 linkc.11G>T p.Arg4Leu missense_variant Exon 2 of 3 ENST00000441259.2 NP_001076585.1 P14222
PRF1NM_005041.6 linkc.11G>T p.Arg4Leu missense_variant Exon 2 of 3 NP_005032.2 P14222

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRF1ENST00000441259.2 linkc.11G>T p.Arg4Leu missense_variant Exon 2 of 3 5 NM_001083116.3 ENSP00000398568.1 P14222

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.95e-7
AC:
1
AN:
1437966
Hom.:
0
Cov.:
34
AF XY:
0.00000140
AC XY:
1
AN XY:
713116
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.0000168
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
0.24
DANN
Benign
0.81
DEOGEN2
Benign
0.18
.;T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.057
N
LIST_S2
Benign
0.40
T;.;T
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.2
.;L;L
PrimateAI
Benign
0.26
T
PROVEAN
Benign
1.2
.;N;N
REVEL
Benign
0.14
Sift
Pathogenic
0.0
.;D;D
Sift4G
Benign
0.69
.;T;T
Polyphen
0.0
.;B;B
Vest4
0.082, 0.074
MutPred
0.27
Loss of methylation at R4 (P = 0.0312);Loss of methylation at R4 (P = 0.0312);Loss of methylation at R4 (P = 0.0312);
MVP
0.51
MPC
0.22
ClinPred
0.42
T
GERP RS
-6.2
Varity_R
0.054
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-72360648; API