chr17-4945982-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_005022.4(PFN1):c.341T>C(p.Met114Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M114R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005022.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PFN1 | NM_005022.4 | c.341T>C | p.Met114Thr | missense_variant | 3/3 | ENST00000225655.6 | |
PFN1 | NM_001375991.1 | c.*425T>C | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PFN1 | ENST00000225655.6 | c.341T>C | p.Met114Thr | missense_variant | 3/3 | 1 | NM_005022.4 | P1 | |
PFN1 | ENST00000574872.1 | c.233T>C | p.Met78Thr | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 18 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 23, 2012 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2021 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PFN1 function (PMID: 22801503). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 37035). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 22801503). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the PFN1 protein (p.Met114Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at