rs885822

Positions:

• chr10-70598821-G-A
• chr10-70598821-G-C
• chr10-70598821-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -2.15

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 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	UniProt
PRF1	NM_001083116.3	c.900C>T	p.His300=	synonymous_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6	c.900C>T	p.His300=	synonymous_variant	3/3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101343 AN: 152030 Hom.: 34448 Cov.: 33

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

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

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.: 33 AF XY: 0.668 AC XY: 49665 AN XY: 74380

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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -

not specified Benign:4

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	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, 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 -

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	-0.95
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

Other links and lift over

dbSNP: rs885822; hg19: chr10-72358577; COSMIC: COSV64615053;