rs885822

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001083116.3(PRF1):c.900C>T(p.His300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,614,034 control chromosomes in the GnomAD database, including 307,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34484 hom., cov: 33)

Exomes 𝑓: 0.61 ( 272593 hom. )

Consequence

PRF1
NM_001083116.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -2.15

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 10-70598821-G-A is Benign according to our data. Variant chr10-70598821-G-A is described in ClinVar as [Benign]. Clinvar id is 257409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-70598821-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRF1	NM_001083116.3 linkuse as main transcript	c.900C>T	p.His300=	synonymous_variant	3/3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6 linkuse as main transcript	c.900C>T	p.His300=	synonymous_variant	3/3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2 linkuse as main transcript	c.900C>T	p.His300=	synonymous_variant	3/3	5	NM_001083116.3	ENSP00000398568	P1

Frequencies

GnomAD3 genomes

AF:

0.667

AC:

101343

AN:

152030

Hom.:

34448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.806

Gnomad AMI

AF:

0.576

Gnomad AMR

AF:

0.643

Gnomad ASJ

AF:

0.570

Gnomad EAS

AF:

0.742

Gnomad SAS

AF:

0.620

Gnomad FIN

AF:

0.658

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.593

Gnomad OTH

AF:

0.642

GnomAD3 exomes

AF:

0.637

AC:

160204

AN:

251422

Hom.:

51801

AF XY:

0.628

AC XY:

85301

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.807

Gnomad AMR exome

AF:

0.682

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.764

Gnomad SAS exome

AF:

0.617

Gnomad FIN exome

AF:

0.648

Gnomad NFE exome

AF:

0.589

Gnomad OTH exome

AF:

0.626

GnomAD4 exome

AF:

0.609

AC:

889918

AN:

1461886

Hom.:

272593

Cov.:

106

AF XY:

0.608

AC XY:

442233

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.810

Gnomad4 AMR exome

AF:

0.676

Gnomad4 ASJ exome

AF:

0.569

Gnomad4 EAS exome

AF:

0.737

Gnomad4 SAS exome

AF:

0.618

Gnomad4 FIN exome

AF:

0.642

Gnomad4 NFE exome

AF:

0.593

Gnomad4 OTH exome

AF:

0.619

GnomAD4 genome

AF:

0.667

AC:

101431

AN:

152148

Hom.:

34484

Cov.:

AF XY:

0.668

AC XY:

49665

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.806

Gnomad4 AMR

AF:

0.643

Gnomad4 ASJ

AF:

0.570

Gnomad4 EAS

AF:

0.742

Gnomad4 SAS

AF:

0.620

Gnomad4 FIN

AF:

0.658

Gnomad4 NFE

AF:

0.593

Gnomad4 OTH

AF:

0.639

Alfa

AF:

0.605

Hom.:

38894

Bravo

AF:

0.673

Asia WGS

AF:

0.633

AC:

2201

AN:

3478

EpiCase

AF:

0.591

EpiControl

AF:

0.581

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2

Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 81% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -

not provided

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lymphoma, non-Hodgkin, familial

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.061

DANN

Benign

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over