rs12161733

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001083116.3(PRF1):c.10C>T(p.Arg4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,587,782 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 4 hom. )

Consequence

PRF1
NM_001083116.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -2.03

Publications

10 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 -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.016731 (below the threshold of 3.09). Trascript score misZ: 0.68523 (below the threshold of 3.09). GenCC associations: The gene is linked to lymphoma, non-Hodgkin, familial, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder, hereditary hemophagocytic lymphohistiocytosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055696666).

BP6

Variant 10-70600893-G-A is Benign according to our data. Variant chr10-70600893-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536220.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00168 (256/152308) while in subpopulation EAS AF = 0.00637 (33/5180). AF 95% confidence interval is 0.00466. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRF1	NM_001083116.3 link	c.10C>T	p.Arg4Cys	missense_variant	Exon 2 of 3	ENST00000441259.2	NP_001076585.1	P14222
PRF1	NM_005041.6 link	c.10C>T	p.Arg4Cys	missense_variant	Exon 2 of 3		NP_005032.2	P14222

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2 link	c.10C>T	p.Arg4Cys	missense_variant	Exon 2 of 3	5	NM_001083116.3	ENSP00000398568.1		P14222

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00636

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000913

AC:

176

AN:

192828

AF XY:

0.000879

show subpopulations

Gnomad AFR exome

AF:

0.00559

Gnomad AMR exome

AF:

0.000252

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00690

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.000199

GnomAD4 exome

AF:

0.000265

AC:

381

AN:

1435474

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

188

AN XY:

711604

show subpopulations

African (AFR)

AF:

0.00526

AC:

175

AN:

33268

American (AMR)

AF:

0.000356

AC:

AN:

39330

Ashkenazi Jewish (ASJ)

AF:

0.0000391

AC:

AN:

25564

East Asian (EAS)

AF:

0.00324

AC:

126

AN:

38910

South Asian (SAS)

AF:

0.0000241

AC:

AN:

82958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50406

Middle Eastern (MID)

AF:

0.000194

AC:

AN:

5142

European-Non Finnish (NFE)

AF:

0.0000309

AC:

AN:

1100358

Other (OTH)

AF:

0.000470

AC:

AN:

59538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00168

AC:

256

AN:

152308

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00503

AC:

209

AN:

41568

American (AMR)

AF:

0.000523

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00637

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000709

Hom.:

Bravo

AF:

0.00177

ESP6500AA

AF:

0.00275

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000806

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aplastic anemia;C1863727:Familial hemophagocytic lymphohistiocytosis 2;C4721532:Lymphoma, non-Hodgkin, familial

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRF1 NM_001083116.2 exon 2 p.Arg4Cys (c.10C>T): This variant has been reported in the literature in at least 3 individuals with hemophagocytic lymphohistiocytosis (HLH) and in two individuals with lymphoma; however, none of these individuals carried a second clearly disease-causing variant in the gene (My 2010 PMID:19863536, Zhang 2011 PMID:21881043, Chen 2017 PMID:29113160). This variant is also present in 0.6% (112/16344) of East Asian alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/10-72360649-G-A). This variant is present in ClinVar (Variation ID:536220). This variant amino acid (Cys) is present in several species including multiple primates and other mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Benign:1

Jun 16, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PRF1-related disorder

Benign:1

Mar 11, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial hemophagocytic lymphohistiocytosis 2

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

5.2

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

.;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.52

T;.;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.2

.;L;L

PhyloP100

-2.0

PrimateAI

Benign

0.26

PROVEAN

Benign

0.47

.;N;N

REVEL

Benign

0.18

Sift

Pathogenic

0.0

.;D;D

Sift4G

Benign

0.21

.;T;T

Polyphen

0.0

.;B;B

Vest4

0.086, 0.070

MVP

0.44

MPC

0.44

ClinPred

0.022

GERP RS

-7.1

Varity_R

0.10

gMVP

0.61

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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