rs775966864

Variant names:

• chr10-70598972-G-A
• rs775966864
• NM_001083116.3:c.749C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70598972-G-A
• chr10-70598972-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001083116.3(PRF1):​c.749C>T​(p.Thr250Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T250T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.33
• Publications: 9 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 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 lymphoma, non-Hodgkin, familial, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder, hereditary hemophagocytic lymphohistiocytosis.

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.749C>T	p.Thr250Met	missense	Exon 3 of 3	NP_001076585.1
	PRF1	NM_005041.6		c.749C>T	p.Thr250Met	missense	Exon 3 of 3	NP_005032.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	ENST00000441259.2	TSL:5 MANE Select	c.749C>T	p.Thr250Met	missense	Exon 3 of 3	ENSP00000398568.1
	PRF1	ENST00000373209.2	TSL:1	c.749C>T	p.Thr250Met	missense	Exon 3 of 3	ENSP00000362305.1
	PALD1	ENST00000697571.1		c.2503G>A	p.Val835Met	missense	Exon 20 of 21	ENSP00000513342.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251396 AF XY: 0.0000368

Gnomad AFR exome AF: 0.000123

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461878 Hom.: 0 Cov.: 35 AF XY: 0.0000358 AC XY: 26 AN XY: 727246

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

African (AFR) AF: 0.000121 AC: 5 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68048

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Uncertain:2

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 250 of the PRF1 protein (p.Thr250Met). This variant is present in population databases (rs775966864, gnomAD 0.02%). 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: 566088). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PRF1 protein function with a positive predictive value of 95%. 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.

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PRF1 p.Thr250Met variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs775966864), Cosmic and ClinVar (classified as a VUS by Invitae for Hemophagocytic lymphohistiocytosis, familial, 2). The variant was also identified in control databases in 12 of 282802 chromosomes at a frequency of 0.000042 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24972 chromosomes (freq: 0.00016), South Asian in 3 of 30616 chromosomes (freq: 0.000098), East Asian in 1 of 19954 chromosomes (freq: 0.00005) and European (non-Finnish) in 4 of 129114 chromosomes (freq: 0.000031), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Thr250 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.3
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.93
MPC		0.54
ClinPred		0.55	D
GERP RS		4.8
Varity_R		0.48
gMVP		0.80
Mutation Taster		=87/13	polymorphism

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: rs775966864; hg19: chr10-72358728; COSMIC: COSV64615200;