rs35329429
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001083116.3(PRF1):c.726C>T(p.Cys242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,614,158 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.012 ( 35 hom., cov: 33)
Exomes 𝑓: 0.0013 ( 33 hom. )
Consequence
PRF1
NM_001083116.3 synonymous
NM_001083116.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.237
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 made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 10-70598995-G-A is Benign according to our data. Variant chr10-70598995-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.237 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1782/152334) while in subpopulation AFR AF= 0.0389 (1617/41568). AF 95% confidence interval is 0.0373. There are 35 homozygotes in gnomad4. There are 816 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 35 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.726C>T | p.Cys242= | synonymous_variant | 3/3 | ENST00000441259.2 | NP_001076585.1 | |
PRF1 | NM_005041.6 | c.726C>T | p.Cys242= | synonymous_variant | 3/3 | NP_005032.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.726C>T | p.Cys242= | synonymous_variant | 3/3 | 5 | NM_001083116.3 | ENSP00000398568 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0116 AC: 1773AN: 152216Hom.: 34 Cov.: 33
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GnomAD3 exomes AF: 0.00309 AC: 777AN: 251228Hom.: 10 AF XY: 0.00233 AC XY: 317AN XY: 135786
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GnomAD4 exome AF: 0.00132 AC: 1927AN: 1461824Hom.: 33 Cov.: 35 AF XY: 0.00114 AC XY: 831AN XY: 727212
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GnomAD4 genome AF: 0.0117 AC: 1782AN: 152334Hom.: 35 Cov.: 33 AF XY: 0.0110 AC XY: 816AN XY: 74494
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 2 Benign:2
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. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Lymphoma, non-Hodgkin, familial Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Autoinflammatory syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 04, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at