rs104894176

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001083116.3(PRF1):c.1122G>A(p.Trp374*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000155 in 1,612,474 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PRF1
NM_001083116.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 5.19

Publications

27 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]

PRF1 links:

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]

PALD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 46 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-70598599-C-T is Pathogenic according to our data. Variant chr10-70598599-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRF1	NM_001083116.3 link	c.1122G>A	p.Trp374*	stop_gained	Exon 3 of 3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6 link	c.1122G>A	p.Trp374*	stop_gained	Exon 3 of 3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2 link	c.1122G>A	p.Trp374*	stop_gained	Exon 3 of 3	5	NM_001083116.3	ENSP00000398568.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

245272

AF XY:

0.0000150

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000363

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460280

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726500

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52222

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111802

Other (OTH)

AF:

0.00

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000709

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2

Pathogenic:9Other:1

Jan 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jul 15, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Aug 06, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000013709 /PMID: 10583959 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

May 04, 2016

Genetic Diagnostics Department, Viafet Genomics Laboratory

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Viafet Genomics Laboratory has identified this variant in a homozygous state in a child presenting with sepsis-like syndrome, hepatosplenomegaly, hypofibrinogenemia, hypoalbuminemia, hypertriglyceridemia, pancytopenia, a very high ferritin level and high direct bilirubin level. In addition, this variant has been identified in a homozygous state in patients affected with familial hemophagocytic lymphohistiocytosis (PMIDs: 10583959 and 20197201). This variant is present in exon 2/2 in a position that is conserved across both transcripts of this gene (2/2). Several loss-of-function variants are reported as disease-causing in HGMD and/or ClinVar after this position.

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

High prevalence in Turkish persons [Zur Stadt et al 2006]

Dec 30, 2017

Department of Genetics, Sultan Qaboos University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Jun 13, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp374*) in the PRF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the PRF1 protein. This variant is present in population databases (rs104894176, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 10583959, 11565555, 16278825, 20197201). ClinVar contains an entry for this variant (Variation ID: 13709). This variant disrupts a region of the PRF1 protein in which other variant(s) (p.Cys497*) have been determined to be pathogenic (PMID: 11841437). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This nonsense variant is found in the last exon of PRF1 and is therefore predicted to escape nonsense-mediated mRNA decay (NMD). However, nonsense variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 17873118). This is a known Pathogenic variant that has been previously reported as a homozygous change in patients with familial hemophagocytic lymphohistiocytosis (PMID: 10583959, 20197201, 33746956). Loss-of-function variation in PRF1 is an established mechanism of disease (PMID: 17873118). The c.1122G>A (p.Trp374Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/245272) and thus is presumed to be rare. Based on the available evidence, the c.1122G>A (p.Trp374Ter) variant is classified as Pathogenic.

not provided

Pathogenic:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 08, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 09, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 182 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 12229880, 12764739, 23274377, 20197201, 10583959, 15728124, 31514334, 34083498, 34426522, 31589614, 33746956, 35023663, 16278825)

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aplastic anemia

Pathogenic:1

Mar 11, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Jun 05, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1122G>A (p.W374*) alteration, located in exon 3 (coding exon 2) of the PRF1 gene, consists of a G to A substitution at nucleotide position 1122. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 374. This alteration occurs at the 3' terminus of the PRF1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 33% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD) database, the PRF1 c.1122G>A alteration was observed in 0.0016% (4/245272) of total alleles studied, with a frequency of 0.0036% (4/110234) in the European (non-Finnish) subpopulation. This alteration has been reported in the homozygous state in several patients with familial hemophagocytic lymphohistiocytosis and is seen more frequently in the Turkish population (Stepp, 1999; Zur Stadt, 2006; Balta, 2010). Cells from an affected patient showed greatly reduced cytolytic activity and complete absence of perforin protein (Stepp, 1999). This alteration has also been reported in the compound heterozygous state in an Omani patient with familial hemophagocytic lymphohistiocytosis (Muralitharan, 2007). Based on the available evidence, this alteration is classified as pathogenic.

Aplastic anemia;C1863727:Familial hemophagocytic lymphohistiocytosis 2;C4721532:Lymphoma, non-Hodgkin, familial

Pathogenic:1

Jan 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autoinflammatory syndrome

Pathogenic:1

Apr 17, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

5.2

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.93

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over