rs12161733

chr10-70600893-G-Achr10-70600893-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001083116.3(PRF1):c.10C>T(p.Arg4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,587,782 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.03

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055696666).
• BP6: Variant 10-70600893-G-A is Benign according to our data. Variant chr10-70600893-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536220.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr10-70600893-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00168 (256/152308) while in subpopulation EAS AF= 0.00637 (33/5180). AF 95% confidence interval is 0.00466. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.10C>T	p.Arg4Cys	missense_variant	2/3	ENST00000441259.2
PRF1	NM_005041.6	c.10C>T	p.Arg4Cys	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.10C>T	p.Arg4Cys	missense_variant	2/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00636

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000913 AC: 176 AN: 192828 Hom.: 1 AF XY: 0.000879 AC XY: 92 AN XY: 104624

Gnomad AFR exome AF: 0.00559

Gnomad AMR exome AF: 0.000252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00690

Gnomad SAS exome AF: 0.0000379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.000199

GnomAD4 exome AF: 0.000265 AC: 381 AN: 1435474 Hom.: 4 Cov.: 34 AF XY: 0.000264 AC XY: 188 AN XY: 711604

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.000356

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.00324

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000309

Gnomad4 OTH exome AF: 0.000470

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74472

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000748 Hom.: 0

Bravo AF: 0.00177

ESP6500AA AF: 0.00275 AC: 12

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000806 AC: 97

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

PRF1 NM_001083116.2 exon 2 p.Arg4Cys (c.10C>T): This variant has been reported in the literature in at least 3 individuals with hemophagocytic lymphohistiocytosis (HLH) and in two individuals with lymphoma; however, none of these individuals carried a second clearly disease-causing variant in the gene (My 2010 PMID:19863536, Zhang 2011 PMID:21881043, Chen 2017 PMID:29113160). This variant is also present in 0.6% (112/16344) of East Asian alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/10-72360649-G-A). This variant is present in ClinVar (Variation ID:536220). This variant amino acid (Cys) is present in several species including multiple primates and other mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 16, 2021

- -

PRF1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial hemophagocytic lymphohistiocytosis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	5.2
Dann	Uncertain	0.98
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.52	T;.;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
Polyphen		0.0	.;B;B
Vest4		0.086, 0.070
MVP		0.44
MPC		0.44
ClinPred		0.022	T
GERP RS		-7.1
Varity_R		0.10
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12161733; hg19: chr10-72360649;