10-70598821-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -2.15

Publications

54 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.900C>T	p.His300His	synonymous_variant	Exon 3 of 3	ENST00000441259.2	NP_001076585.1	P14222
PRF1	NM_005041.6 link	c.900C>T	p.His300His	synonymous_variant	Exon 3 of 3		NP_005032.2	P14222

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2 link	c.900C>T	p.His300His	synonymous_variant	Exon 3 of 3	5	NM_001083116.3	ENSP00000398568.1		P14222

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

GnomAD2 exomes

AF:

0.637

AC:

160204

AN:

251422

AF XY:

0.628

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 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

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

26877

53754

80630

107507

134384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18172

36344

54516

72688

90860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.667

AC:

101431

AN:

152148

Hom.:

34484

Cov.:

AF XY:

0.668

AC XY:

49665

AN XY:

74380

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1724

3448

5171

6895

8619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

796

1592

2388

3184

3980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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:1Other: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

(source)

DANN

Benign

0.41

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over