chr10-70599048-G-A

Variant names:

• chr10-70599048-G-A
• rs28933973
• NM_001083116.3:c.673C>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001083116.3(PRF1):​c.673C>T​(p.Arg225Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,136 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 (★★). ClinVar reports functional evidence for this variant: "SCV000363433: Functional studies demonstrated that the variant results in decreased or absent perforin expression and reduced NK cell cytolytic activity (Stepp et al. 1999" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.273
• Publications: 25 publications found

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

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000363433: Functional studies demonstrated that the variant results in decreased or absent perforin expression and reduced NK cell cytolytic activity (Stepp et al. 1999; Risma et al. 2004; Voskoboinik et al. 2004; Trizzino et al. 2008).; SCV002234638: Experimental studies have shown that this missense change affects PRF1 function (PMID: 15365097).; SCV004100919: Experimental studies have shown that this missense change affects PRF1 function Voskoboinik I, et al., 2004.; SCV002570678: Experimental studies have shown that the variant is associated with reduced or absent expression of the mature protein and severely impaired NK function (e.g. Stepp_1999, Voskoboinik_2004, Risma_2006).; SCV003556362: Cells from an affected patient showed nearly complete absence of perforin and greatly reduced cytolytic activity (Stepp, 1999; Feldmann, 2002). In addition, in vitro functional studies of the p.R225W alteration demonstrated abnormal protein function including loss of cytolytic activity, failure to traffic to rat basophil leukemia secretory granules, diminished perforin detection, and no apparent proteolytic maturation. Voskoboinik, 2004; Risma, 2006).; SCV005439060: Experimental studies have shown that this missense change affects PRF1 function Voskoboinik I, et al., 2004.
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001083116.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.016731 (below the threshold of 3.09). Trascript score misZ: 0.68523 (below the threshold of 3.09). GenCC associations: The gene is linked to familial hemophagocytic lymphohistiocytosis 2, lymphoma, non-Hodgkin, familial, hereditary hemophagocytic lymphohistiocytosis, fatal post-viral neurodegenerative disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-70599048-G-A is Pathogenic according to our data. Variant chr10-70599048-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083116.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	NM_001083116.3	MANE Select	c.673C>T	p.Arg225Trp	missense	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.673C>T	p.Arg225Trp	missense	Exon 3 of 3	NP_005032.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	ENST00000441259.2	TSL:5 MANE Select	c.673C>T	p.Arg225Trp	missense	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.673C>T	p.Arg225Trp	missense	Exon 3 of 3	ENSP00000362305.1	P14222
	PALD1	ENST00000697571.1		c.2579G>A	p.Arg860Gln	missense	Exon 20 of 21	ENSP00000513342.1	A0A8V8TMP9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249622 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461136 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726754

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111504

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000161 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Familial hemophagocytic lymphohistiocytosis 2 (6)
1	-	-	Aplastic anemia (1)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	Familial hemophagocytic lymphohistiocytosis (1)
1	-	-	Familial hemophagocytic lymphohistiocytosis type 1 (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.093
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.27
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.91		Loss of methylation at R225 (P = 0.0393)
MVP		0.88
MPC		0.14
ClinPred		0.90	D
GERP RS		2.3
Varity_R		0.30
gMVP		0.83
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28933973; hg19: chr10-72358804; COSMIC: COSV64615781;