10-70598721-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001083116.3(PRF1):c.1000G>A(p.Gly334Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001083116.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.1000G>A | p.Gly334Ser | missense_variant | 3/3 | ENST00000441259.2 | NP_001076585.1 | |
PRF1 | NM_005041.6 | c.1000G>A | p.Gly334Ser | missense_variant | 3/3 | NP_005032.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.1000G>A | p.Gly334Ser | missense_variant | 3/3 | 5 | NM_001083116.3 | ENSP00000398568.1 |
Frequencies
GnomAD3 genomes AF: 0.000374 AC: 57AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000450 AC: 113AN: 251062Hom.: 0 AF XY: 0.000413 AC XY: 56AN XY: 135748
GnomAD4 exome AF: 0.000386 AC: 565AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.000388 AC XY: 282AN XY: 727226
GnomAD4 genome AF: 0.000374 AC: 57AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; Reported in study on families with breast cancer, however segregation and clinical information were not provided (PMID: 27153395); This variant is associated with the following publications: (PMID: 34426522, 19484379, 23592409, 27153395) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Familial hemophagocytic lymphohistiocytosis 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2023 | Variant summary: PRF1 c.1000G>A (p.Gly334Ser) results in a non-conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251062 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00045 vs 0.0027), allowing no conclusion about variant significance. c.1000G>A has been reported in the literature in an individual(s) affected with Familial Hemophagocytic Lymphohistiocytosis without strong evidence of causality (Poltavets_2008). This report does not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19484379). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2021 | The c.1000G>A (p.G334S) alteration is located in exon 3 (coding exon 2) of the PRF1 gene. This alteration results from a G to A substitution at nucleotide position 1000, causing the glycine (G) at amino acid position 334 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at