rs28933374
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_001083116.3(PRF1):c.1034C>T(p.Pro345Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P345R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001083116.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRF1 | NM_001083116.3 | c.1034C>T | p.Pro345Leu | missense_variant | 3/3 | ENST00000441259.2 | |
PRF1 | NM_005041.6 | c.1034C>T | p.Pro345Leu | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRF1 | ENST00000441259.2 | c.1034C>T | p.Pro345Leu | missense_variant | 3/3 | 5 | NM_001083116.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250518Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135538
GnomAD4 exome Cov.: 33
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 03, 1999 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 06, 2022 | Variant summary: PRF1 c.1034C>T (p.Pro345Leu) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250518 control chromosomes. c.1034C>T has been reported in the literature as a homozygous genotype in at-least one individual affected with Familial Hemophagocytic Lymphohistiocytosis who has been subsequently cited by others (example, Stepp_1999 cited in Feldmann_2002, Lucchini_2018, Ishii_2005, An_2013, Benezech_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at