Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_001083116.3(PRF1):c.548T>G(p.Val183Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V183V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PRF1
NM_001083116.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.07

Publications

5 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

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 lymphoma, non-Hodgkin, familial, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder, hereditary hemophagocytic lymphohistiocytosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 10-70599173-A-C is Pathogenic according to our data. Variant chr10-70599173-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13715.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	NM_001083116.3	MANE Select	c.548T>G	p.Val183Gly	missense	Exon 3 of 3	NP_001076585.1
	PRF1	NM_005041.6		c.548T>G	p.Val183Gly	missense	Exon 3 of 3	NP_005032.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRF1	ENST00000441259.2	TSL:5 MANE Select	c.548T>G	p.Val183Gly	missense	Exon 3 of 3	ENSP00000398568.1
PRF1	ENST00000373209.2	TSL:1	c.548T>G	p.Val183Gly	missense	Exon 3 of 3	ENSP00000362305.1
PALD1	ENST00000697571.1		c.*17+89A>C		intron	N/A	ENSP00000513342.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hemophagocytic lymphohistiocytosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.80

Eigen

Benign

0.12

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.50

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.8

PhyloP100

6.1

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.55

Vest4

0.75

MutPred

0.78

Loss of stability (P = 0.0049)

MVP

0.79

MPC

0.41

ClinPred

0.95

GERP RS

5.8

Varity_R

0.86

gMVP

0.82

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs104894183

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over