GeneBe

10-70600695-CG-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001083116.3(PRF1):​c.207delC​(p.Asp70ThrfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRF1
NM_001083116.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -4.83

Publications

4 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]
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]

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-70600695-CG-C is Pathogenic according to our data. Variant chr10-70600695-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13722.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083116.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PRF1
NM_001083116.3
MANE Select
c.207delCp.Asp70ThrfsTer37
frameshift
Exon 2 of 3NP_001076585.1
PRF1
NM_005041.6
c.207delCp.Asp70ThrfsTer37
frameshift
Exon 2 of 3NP_005032.2

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PRF1
ENST00000441259.2
TSL:5 MANE Select
c.207delCp.Asp70ThrfsTer37
frameshift
Exon 2 of 3ENSP00000398568.1
PRF1
ENST00000373209.2
TSL:1
c.207delCp.Asp70ThrfsTer37
frameshift
Exon 2 of 3ENSP00000362305.1
PRF1
ENST00000638674.1
TSL:5
c.207delCp.Asp70ThrfsTer37
frameshift
Exon 2 of 3ENSP00000492048.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461534
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727058
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86232
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53316
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5692
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111908
Other (OTH)
AF:
0.00
AC:
0
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aplastic anemia Pathogenic:1
Sep 08, 2022
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1
May 01, 2003
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
-4.8
Mutation Taster
=5/195
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs786205093; hg19: chr10-72360451; API