rs885821

Variant summary

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

The NM_001083116.3(PRF1):c.822C>T(p.Ala274=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,614,136 control chromosomes in the GnomAD database, including 26,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2187 hom., cov: 33)

Exomes 𝑓: 0.18 ( 24634 hom. )

Consequence

PRF1
NM_001083116.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -3.43

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=-0.85).

BP6

Variant 10-70598899-G-A is Benign according to our data. Variant chr10-70598899-G-A is described in ClinVar as [Benign]. Clinvar id is 257408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-70598899-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3 linkuse as main transcript	c.822C>T	p.Ala274=	synonymous_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6 linkuse as main transcript	c.822C>T	p.Ala274=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2 linkuse as main transcript	c.822C>T	p.Ala274=	synonymous_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23670

AN:

152134

Hom.:

2188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0806

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.0831

Gnomad FIN

AF:

0.292

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.188

Gnomad OTH

AF:

0.148

GnomAD3 exomes

AF:

0.164

AC:

41221

AN:

251390

Hom.:

3869

AF XY:

0.160

AC XY:

21743

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0769

Gnomad AMR exome

AF:

0.147

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.0762

Gnomad FIN exome

AF:

0.287

Gnomad NFE exome

AF:

0.186

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.179

AC:

261665

AN:

1461884

Hom.:

24634

Cov.:

AF XY:

0.176

AC XY:

127861

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0761

Gnomad4 AMR exome

AF:

0.145

Gnomad4 ASJ exome

AF:

0.207

Gnomad4 EAS exome

AF:

0.119

Gnomad4 SAS exome

AF:

0.0801

Gnomad4 FIN exome

AF:

0.276

Gnomad4 NFE exome

AF:

0.189

Gnomad4 OTH exome

AF:

0.166

GnomAD4 genome

AF:

0.155

AC:

23666

AN:

152252

Hom.:

2187

Cov.:

AF XY:

0.157

AC XY:

11708

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0807

Gnomad4 AMR

AF:

0.151

Gnomad4 ASJ

AF:

0.206

Gnomad4 EAS

AF:

0.115

Gnomad4 SAS

AF:

0.0830

Gnomad4 FIN

AF:

0.292

Gnomad4 NFE

AF:

0.188

Gnomad4 OTH

AF:

0.145

Alfa

AF:

0.172

Hom.:

2112

Bravo

AF:

0.141

Asia WGS

AF:

0.102

AC:

353

AN:

3478

EpiCase

AF:

0.181

EpiControl

AF:

0.175

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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 33% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial hemophagocytic lymphohistiocytosis 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Feb 01, 2024	- -

Lymphoma, non-Hodgkin, familial

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

not provided

Other: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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.31

Dann

Benign

0.69

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