rs138126912

chr10-70598411-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_001083116.3(PRF1):c.1310C>T(p.Ala437Val) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,614,020 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 3.63

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001083116.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.1310C>T	p.Ala437Val	missense_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6	c.1310C>T	p.Ala437Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.1310C>T	p.Ala437Val	missense_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000730 AC: 183 AN: 250636 Hom.: 0 AF XY: 0.000708 AC XY: 96 AN XY: 135616

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00112 AC: 1631 AN: 1461730 Hom.: 3 Cov.: 33 AF XY: 0.00108 AC XY: 785 AN XY: 727170

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74456

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.000680

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000807 AC: 98

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 21, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 437 of the PRF1 protein (p.Ala437Val). This variant is present in population databases (rs138126912, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with suspected familial hemophagocytic lymphohistiocytosis (HLH), atypical HLH, and/or lymphoma of the brain (PMID: 21881043, 25845254, 25937001, 29263817). ClinVar contains an entry for this variant (Variation ID: 300327). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 21, 2017	The PRF1 c.1310C>T (p.Ala437Val) missense variant has been reported in five studies in which it was found in a total of six individuals with familial hemophagocytic lymphohistocytosis including in a compound heterozygous state with another missense variant in two individuals and in a heterozygous state where a second variant was not detected in four individuals including one sib-pair. The variant was also found in a heterozygous state in the unaffected father of the sib-pair (Zhang et al. 2011; Zhang et al. 2014; Willig et al. 2015; Džoljić et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Ala437Val variant results in absent NK-cell function and 61% of normal perforin levels (Zhang et al. 2011). Based on the evidence, the p.Ala437Val variant is classified as likely pathogenic for familial hemophagocytic lymphohistocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 25, 2022

Variant summary: PRF1 c.1310C>T (p.Ala437Val) results in a non-conservative amino acid change located in the C2 domain (IPR000008) 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 0.00073 in 250636 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00073 vs 0.0027), allowing no conclusion about variant significance. c.1310C>T has been reported in the literature as a non-informative genotype (second allele not specified) or in a proposed model of synergistic heterozygosity with a heterozygous variant in a different gene in individuals affected with features of Familial Hemophagocytic Lymphohistiocytosis (FHL)/Primary Lymphoma with a family history of FHL/Omphalocele and Liver failure (example, Zhang_2011, Dolji_2015, Noll_2016). These report(s) do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; Likely pathogenic, 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 submitter

clinical testing

Ambry Genetics

Sep 28, 2022

The c.1310C>T (p.A437V) alteration is located in exon 3 (coding exon 2) of the PRF1 gene. This alteration results from a C to T substitution at nucleotide position 1310, causing the alanine (A) at amino acid position 437 to be replaced by a valine (V). The p.A437V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.020	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.69
MVP		0.87
MPC		0.53
ClinPred		0.11	T
GERP RS		4.8
Varity_R		0.59
gMVP		0.69

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

Other links and lift over

dbSNP: rs138126912; hg19: chr10-72358167;