chr10-70598007-A-G
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001083116.3(PRF1):c.*46T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,603,938 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 11 hom. )
Consequence
PRF1
NM_001083116.3 3_prime_UTR
NM_001083116.3 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.250
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00286 (436/152210) while in subpopulation AMR AF= 0.00484 (74/15280). AF 95% confidence interval is 0.00396. There are 1 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 11 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.*46T>C | 3_prime_UTR_variant | 3/3 | ENST00000441259.2 | ||
PRF1 | NM_005041.6 | c.*46T>C | 3_prime_UTR_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.*46T>C | 3_prime_UTR_variant | 3/3 | 5 | NM_001083116.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00287 AC: 436AN: 152092Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00311 AC: 757AN: 243542Hom.: 2 AF XY: 0.00322 AC XY: 426AN XY: 132174
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GnomAD4 exome AF: 0.00316 AC: 4588AN: 1451728Hom.: 11 Cov.: 32 AF XY: 0.00317 AC XY: 2290AN XY: 722616
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GnomAD4 genome AF: 0.00286 AC: 436AN: 152210Hom.: 1 Cov.: 32 AF XY: 0.00288 AC XY: 214AN XY: 74424
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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Name
Calibrated prediction
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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