rs201584464

chr10-70598615-G-Achr10-70598615-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001083116.3(PRF1):c.1106C>T(p.Thr369Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,612,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T369T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.38

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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001083116.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0078881085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.1106C>T	p.Thr369Met	missense_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6	c.1106C>T	p.Thr369Met	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.1106C>T	p.Thr369Met	missense_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000690 AC: 17 AN: 246272 Hom.: 0 AF XY: 0.0000672 AC XY: 9 AN XY: 134026

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000548 AC: 80 AN: 1460524 Hom.: 0 Cov.: 32 AF XY: 0.0000592 AC XY: 43 AN XY: 726630

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74464

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 369 of the PRF1 protein (p.Thr369Met). This variant is present in population databases (rs201584464, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PRF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 570224). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.029
Dann	Benign	0.33
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.018	N
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.71	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.21
Sift	Benign	0.59	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.029	B;B
Vest4		0.12
MVP		0.54
MPC		0.12
ClinPred		0.0079	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.21

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: rs201584464; hg19: chr10-72358371; COSMIC: COSV64615028;