NM_001083116.3:c.112G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_001083116.3(PRF1):​c.112G>T​(p.Val38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,386 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V38M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PRF1
NM_001083116.3 missense

Scores

10
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

Publications

6 publications found
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 was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001083116.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.016731 (below the threshold of 3.09). Trascript score misZ: 0.68523 (below the threshold of 3.09). GenCC associations: The gene is linked to lymphoma, non-Hodgkin, familial, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder, hereditary hemophagocytic lymphohistiocytosis.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRF1NM_001083116.3 linkc.112G>T p.Val38Leu missense_variant Exon 2 of 3 ENST00000441259.2 NP_001076585.1 P14222
PRF1NM_005041.6 linkc.112G>T p.Val38Leu 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.112G>T p.Val38Leu missense_variant Exon 2 of 3 5 NM_001083116.3 ENSP00000398568.1 P14222

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458386
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
725006
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33432
American (AMR)
AF:
0.00
AC:
0
AN:
44570
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25956
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39608
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86002
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53146
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5734
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1109752
Other (OTH)
AF:
0.00
AC:
0
AN:
60186
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
17
DANN
Benign
0.95
DEOGEN2
Uncertain
0.59
.;D;D
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.30
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.61
T;.;T
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.56
D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.5
.;M;M
PhyloP100
1.6
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-2.2
.;N;N
REVEL
Uncertain
0.37
Sift
Benign
0.081
.;T;T
Sift4G
Uncertain
0.031
.;D;D
Polyphen
0.43
.;B;B
Vest4
0.16, 0.14
MutPred
0.78
Gain of disorder (P = 0.1993);Gain of disorder (P = 0.1993);Gain of disorder (P = 0.1993);
MVP
0.82
MPC
0.19
ClinPred
0.23
T
GERP RS
2.8
Varity_R
0.098
gMVP
0.92
Mutation Taster
=66/34
polymorphism

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

Other links and lift over

dbSNP: rs201909472; hg19: chr10-72360547; API