rs751247865

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001083116.3(PRF1):c.666C>A(p.His222Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,424 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PRF1
NM_001083116.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:2

Conservation

PhyloP100: 0.507

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 made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001083116.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 10-70599055-G-T is Pathogenic according to our data. Variant chr10-70599055-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3 linkuse as main transcript	c.666C>A	p.His222Gln	missense_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6 linkuse as main transcript	c.666C>A	p.His222Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2 linkuse as main transcript	c.666C>A	p.His222Gln	missense_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152250

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249592

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134960

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000802

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461174

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726762

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:

0.0000378

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	The H222Q pathogenic variant in the PRF1 gene has been reported previously in individuals with familial hemophagocytic lymphohistiocytosis, in both the homozygous and compound heterozygous states (Molleran et al., 2004; Zur Stadt et al., 2006; Bryceson et al., 2007). Functional studies found that cells expressing the H222Q variant had no detectable cytotoxic activity (Voskoboinik et al., 2005; Chia et al., 2009). The H222Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H222Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. We interpret H222Q as a pathogenic variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Aplastic anemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

Familial hemophagocytic lymphohistiocytosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 15, 2022

Variant summary: PRF1 c.666C>A (p.His222Gln) results in a non-conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249592 control chromosomes (gnomAD). c.666C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis and the variant segregated with the disease (examples: Karandikar_2007 and Vermeulen_2009, Voskoboinik_2005, Chia_2009). These data indicate that the variant is very likely to be associated with disease. Functional studies showed this variant results in normal expression of perforin but no detectable cytotoxic activity in transfected cells (Voskoboinik_2005, Chia_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Familial hemophagocytic lymphohistiocytosis 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 222 of the PRF1 protein (p.His222Gln). This variant is present in population databases (rs751247865, gnomAD 0.01%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 14757862, 15205266, 16278825, 17525286, 19595804). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280112). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRF1 protein function. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15755897, 17525286, 19487666). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.45

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.79

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.5

H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-8.0

D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.98

Gain of catalytic residue at H222 (P = 0.0617);Gain of catalytic residue at H222 (P = 0.0617);

MVP

0.93

MPC

0.54

ClinPred

0.99

GERP RS

2.7

Varity_R

0.94

gMVP

0.96

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over