10-70598966-T-C

Position:

chr10-70598966-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001083116.3(PRF1):c.755A>G(p.Asn252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,614,236 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N252N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 42 hom. )

Consequence

PRF1
NM_001083116.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: 0.935

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 -11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001083116.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0023942888).

BP6

Variant 10-70598966-T-C is Benign according to our data. Variant chr10-70598966-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13716.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=5}. Variant chr10-70598966-T-C is described in Lovd as [Benign]. Variant chr10-70598966-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00746 (1136/152350) while in subpopulation AFR AF= 0.00928 (386/41590). AF 95% confidence interval is 0.00852. There are 18 homozygotes in gnomad4. There are 519 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3 linkuse as main transcript	c.755A>G	p.Asn252Ser	missense_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6 linkuse as main transcript	c.755A>G	p.Asn252Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2 linkuse as main transcript	c.755A>G	p.Asn252Ser	missense_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00742

AC:

1130

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00921

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00682

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00503

AC:

1264

AN:

251430

Hom.:

AF XY:

0.00466

AC XY:

633

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00898

Gnomad AMR exome

AF:

0.00567

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00542

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00631

AC:

9221

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00619

AC XY:

4501

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0100

Gnomad4 AMR exome

AF:

0.00617

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00531

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.00692

Gnomad4 OTH exome

AF:

0.00621

GnomAD4 genome

AF:

0.00746

AC:

1136

AN:

152350

Hom.:

Cov.:

AF XY:

0.00697

AC XY:

519

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00928

Gnomad4 AMR

AF:

0.00758

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00682

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00661

Hom.:

Bravo

AF:

0.00831

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.00517

AC:

628

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00649

EpiControl

AF:

0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PRF1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15728124, 18198357, 18496551, 22995991, 24309606, 20981092, 23592409, 25569260, 27153395, 29146883, 32659967, 32356861, 32198610, 32098966, 10583959, 34938098, 15459303, 15659737, 15755897) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 17, 2022	Variant summary: PRF1 c.755A>G (p.Asn252Ser) results in a conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 282834 control chromosomes in the gnomAD database, including 9 homozygotes; occuring predominantly at a frequency of 0.0087 within the African or African-American subpopulation in the gnomAD database, with 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, three as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Aug 14, 2017	BS1, BS4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is a variant that did not show segregation with affected members of a family (PMID: 15659737), and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial hemophagocytic lymphohistiocytosis 2

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.2

DANN

Benign

0.58

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.53

.;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.20

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.59

N;N

REVEL

Benign

0.21

Sift

Benign

0.20

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0

B;B

Vest4

0.041

MVP

0.71

MPC

0.087

ClinPred

0.0042

GERP RS

4.7

Varity_R

0.064

gMVP

0.52

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