rs193302875

chr10-70598558-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S388R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P: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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a disulfide_bond (size 166) in uniprot entity PERF_HUMAN there are 23 pathogenic changes around while only 5 benign (82%) in NM_001083116.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-70598558-C-A is Pathogenic according to our data. Variant chr10-70598558-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13719.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.1163G>T	p.Ser388Ile	missense_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aplastic anemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 2007

- -

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
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	9.5e-8	A;A;A
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;