rs885822

Variant names:

• chr10-70598821-G-A
• rs885822
• NM_001083116.3:c.900C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083116.3(PRF1):​c.900C>T​(p.His300His) 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:12 O:1
• Conservation: PhyloP100: -2.15
• Publications: 54 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: Benign. The variant received -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 VariationId is 257409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.900C>T	p.His300His	synonymous_variant	Exon 3 of 3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.900C>T	p.His300His	synonymous_variant	Exon 3 of 3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2	c.900C>T	p.His300His	synonymous_variant	Exon 3 of 3	5	NM_001083116.3	ENSP00000398568.1

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

GnomAD2 exomes AF: 0.637 AC: 160204 AN: 251422 AF XY: 0.628

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 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

African (AFR) AF: 0.810 AC: 27113 AN: 33480

American (AMR) AF: 0.676 AC: 30218 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14877 AN: 26136

East Asian (EAS) AF: 0.737 AC: 29240 AN: 39700

South Asian (SAS) AF: 0.618 AC: 53265 AN: 86258

European-Finnish (FIN) AF: 0.642 AC: 34307 AN: 53418

Middle Eastern (MID) AF: 0.639 AC: 3683 AN: 5768

European-Non Finnish (NFE) AF: 0.593 AC: 659856 AN: 1112008

Other (OTH) AF: 0.619 AC: 37359 AN: 60394

GnomAD4 genome AF: 0.667 AC: 101431 AN: 152148 Hom.: 34484 Cov.: 33 AF XY: 0.668 AC XY: 49665 AN XY: 74380

African (AFR) AF: 0.806 AC: 33469 AN: 41504

American (AMR) AF: 0.643 AC: 9844 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1977 AN: 3466

East Asian (EAS) AF: 0.742 AC: 3830 AN: 5164

South Asian (SAS) AF: 0.620 AC: 2988 AN: 4820

European-Finnish (FIN) AF: 0.658 AC: 6975 AN: 10598

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40300 AN: 67974

Other (OTH) AF: 0.639 AC: 1351 AN: 2114

Alfa AF: 0.625 Hom.: 56872

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:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Benign:6

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Lymphoma, non-Hodgkin, familial Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical 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
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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