rs193302875

Positions:

• chr10-70598558-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001083116.3(PRF1):​c.1163G>T​(p.Ser388Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: -0.377

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]

PRF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.1163G>T	p.Ser388Ile	missense_variant	3/3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.1163G>T	p.Ser388Ile	missense_variant	3/3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2	c.1163G>T	p.Ser388Ile	missense_variant	3/3	5	NM_001083116.3	ENSP00000398568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aplastic anemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 2007

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 23, 2024

Variant summary: PRF1 c.1163G>T (p.Ser388Ile) results in a non-conservative amino acid change located in the Perforin-1, C2 domain (IPR037300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246806 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1163G>T has been reported in the literature in the presumed compound heterozygous state with the p.Ala91Val variant (Likely Benign by our laboratory) in at least 1 individual affected with clinical features of Familial Hemophagocytic Lymphohistiocytosis and loss of detectable perforin protein (example, Solomou_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. Cytolytic activity in patient cells was reduced vs. controls (example, Solomou_2007), however the impact of this variant alone could not be determined. The following publication has been ascertained in the context of this evaluation (PMID: 17311987). ClinVar contains an entry for this variant (Variation ID: 13719). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.62	.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;D
Vest4		0.24
MutPred		0.23		Loss of phosphorylation at S388 (P = 0.0145);Loss of phosphorylation at S388 (P = 0.0145);
MVP		0.85
MPC		0.51
ClinPred		0.98	D
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.60

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: rs193302875; hg19: chr10-72358314;