rs147035858

Positions:

• chr10-70600852-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001083116.3(PRF1):​c.50del​(p.Leu17ArgfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,609,230 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: PRF1 NM_001083116.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: -2.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-70600852-CA-C is Pathogenic according to our data. Variant chr10-70600852-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 468305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-70600852-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.50del	p.Leu17ArgfsTer34	frameshift_variant	2/3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.50del	p.Leu17ArgfsTer34	frameshift_variant	2/3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2	c.50del	p.Leu17ArgfsTer34	frameshift_variant	2/3	5	NM_001083116.3	ENSP00000398568	P1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000237 AC: 55 AN: 231966 Hom.: 0 AF XY: 0.000158 AC XY: 20 AN XY: 126318

Gnomad AFR exome AF: 0.00324

Gnomad AMR exome AF: 0.000212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000975

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000892 AC: 130 AN: 1456928 Hom.: 0 Cov.: 34 AF XY: 0.0000745 AC XY: 54 AN XY: 724418

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74472

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000454 Hom.: 0

Bravo AF: 0.00107

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This frameshifting variant in exon 2 of 3 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in PRF1 is an established mechanism of disease (PMID:17873118). This variant has been previously reported as a homozygous and compound heterozygous change in individuals with familial hemophagocytic lymphohistiocytosis (PMID: 10583959, 22437823, 23255033, 29239076, 34083498). The c.50del (p.Leu17ArgfsTer34) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (87/263362) and thus is presumed to be rare. Based on the available evidence, c.50del (p.Leu17ArgfsTer34) is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 03, 2018	The PRF1 c.50delT (p.Leu17ArgfsTer34) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu17ArgfsTer34 variant has been described in four studies in which it is found in a homozygous state in 36 probands and in a compound heterozygous state in 11 probands (Stepp et al. 1999; Lee et al. 2006; Trizzino et al. 2008; Higa et al. 2013). The p.Leu17ArgfsTer34 variant was reported in seven of 58 control chromosomes and is reported at a reported frequency of 0.003926 in the African population of the Exome Aggregation Consortium. Individuals who were homozygous for the variant were found to have absent NK cytolytic activity, individuals who were compound heterozygotes for the variant were shown to have activity levels of between 1 - 5% of wild type. Perforin expression was severely reduced or undetectable (Stepp et al. 1999; Lee et al. 2006; Trizzino et al. 2008; Higa et al. 2013). Haplotype analysis showed that the p.Leu17ArgfsTer34 variant is inherited as part of a common haplotype, commonly seen in affected individuals of African descent associated with an earlier age of onset compared to other variants in the PRF1 gene (Lee et al. 2006). Based on the potential impact of truncating variants and collective evidence, the p.Leu17ArgfsTer34variant is classified as pathogenic for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Leu17Argfs*34) in the PRF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRF1 are known to be pathogenic (PMID: 1156555, 16860143). This variant is present in population databases (rs147035858, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (FHL) (PMID: 10583959, 14757862, 16860143, 17873118, 22437823, 23255033). It is commonly reported in individuals of African ancestry (PMID: 10583959, 14757862, 16860143, 17873118, 22437823, 23255033). ClinVar contains an entry for this variant (Variation ID: 468305). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	High frequency in African American population [Lee et al 2006] -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 01, 2021	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16860143, 10583959, 29239076, 17873118, 23255033, 22437823, 24916509, 30487145, 31395954, 29625052, 32542393, 34083498, 33570715, 14757862, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2021	- -

Aplastic anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 24, 2024

- -

Familial hemophagocytic lymphohistiocytosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 25, 2020

Variant summary: PRF1 c.50delT (p.Leu17ArgfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00024 in 231966 control chromosomes and at a frequency of 0.0032 among individuals of African descent. c.50delT has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Stepp_1999, Sanchez_2012, Higa_2013, Zhang_2014, Wojcik_2019). At-least one of these reports suggests a potential digenic mode of inheritance of FHL as a result of a synergistic function effect within genes involved in cytotoxic lymphocyte degranulation (Zhang_2014). It has also been reported as a well recognized cause of Familial Hemophagocytic Lymphohistiocytosis among individuals of African descent (Lee_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

PRF1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

The PRF1 c.50delT variant is predicted to result in a frameshift and premature protein termination (p.Leu17Argfs*34). This variant has been reported to be causative for recessive familial hemophagocytic lymphohistiocytosis (FHL) in several studies (Stepp et al. 1999. PubMed ID: 10583959; Molleran Lee et al. 2004. PubMed ID: 14757862). This variant has been reported to be found at a high frequency among FHL patients of African descent (Lee et al. 2006. PubMed ID: 16860143), and is reported in 0.34% of alleles in individuals of African descent in gnomAD. Frameshift variants in PRF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Aplastic anemia;C1863727:Familial hemophagocytic lymphohistiocytosis 2;C4721532:Lymphoma, non-Hodgkin, familial Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs147035858; hg19: chr10-72360608;