10-70598721-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001083116.3(PRF1):​c.1000G>A​(p.Gly334Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

PRF1
NM_001083116.3 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: -0.832
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007969499).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRF1NM_001083116.3 linkuse as main transcriptc.1000G>A p.Gly334Ser missense_variant 3/3 ENST00000441259.2 NP_001076585.1 P14222
PRF1NM_005041.6 linkuse as main transcriptc.1000G>A p.Gly334Ser missense_variant 3/3 NP_005032.2 P14222

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRF1ENST00000441259.2 linkuse as main transcriptc.1000G>A p.Gly334Ser missense_variant 3/35 NM_001083116.3 ENSP00000398568.1 P14222

Frequencies

GnomAD3 genomes
AF:
0.000374
AC:
57
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000514
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000450
AC:
113
AN:
251062
Hom.:
0
AF XY:
0.000413
AC XY:
56
AN XY:
135748
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000636
Gnomad ASJ exome
AF:
0.00239
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000555
Gnomad NFE exome
AF:
0.000423
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000386
AC:
565
AN:
1461848
Hom.:
0
Cov.:
32
AF XY:
0.000388
AC XY:
282
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000581
Gnomad4 ASJ exome
AF:
0.00295
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.000431
Gnomad4 NFE exome
AF:
0.000360
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.000374
AC:
57
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00317
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000514
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000501
Hom.:
0
Bravo
AF:
0.000366
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000387
AC:
47
EpiCase
AF:
0.000818
EpiControl
AF:
0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 21, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; Reported in study on families with breast cancer, however segregation and clinical information were not provided (PMID: 27153395); This variant is associated with the following publications: (PMID: 34426522, 19484379, 23592409, 27153395) -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Familial hemophagocytic lymphohistiocytosis 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 10, 2023Variant summary: PRF1 c.1000G>A (p.Gly334Ser) results in a non-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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251062 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00045 vs 0.0027), allowing no conclusion about variant significance. c.1000G>A has been reported in the literature in an individual(s) affected with Familial Hemophagocytic Lymphohistiocytosis without strong evidence of causality (Poltavets_2008). This report does not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19484379). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2021The c.1000G>A (p.G334S) alteration is located in exon 3 (coding exon 2) of the PRF1 gene. This alteration results from a G to A substitution at nucleotide position 1000, causing the glycine (G) at amino acid position 334 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
0.55
DANN
Benign
0.56
DEOGEN2
Benign
0.14
T;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.059
N
LIST_S2
Benign
0.45
.;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.0080
T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
-1.7
N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
2.2
N;N
REVEL
Uncertain
0.44
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0020
B;B
Vest4
0.073
MVP
0.33
MPC
0.11
ClinPred
0.0063
T
GERP RS
-1.1
Varity_R
0.039
gMVP
0.26

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: rs145463632; hg19: chr10-72358477; API