rs140547520
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_005022.4(PFN1):āc.350A>Gā(p.Glu117Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,613,144 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E117D) has been classified as Likely benign.
Frequency
Consequence
NM_005022.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PFN1 | NM_005022.4 | c.350A>G | p.Glu117Gly | missense_variant | 3/3 | ENST00000225655.6 | |
PFN1 | NM_001375991.1 | c.*434A>G | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PFN1 | ENST00000225655.6 | c.350A>G | p.Glu117Gly | missense_variant | 3/3 | 1 | NM_005022.4 | P1 | |
PFN1 | ENST00000574872.1 | c.242A>G | p.Glu81Gly | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000566 AC: 86AN: 152048Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000497 AC: 125AN: 251482Hom.: 0 AF XY: 0.000544 AC XY: 74AN XY: 135918
GnomAD4 exome AF: 0.00115 AC: 1673AN: 1460978Hom.: 1 Cov.: 29 AF XY: 0.00108 AC XY: 786AN XY: 726870
GnomAD4 genome ? AF: 0.000565 AC: 86AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40AN XY: 74400
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2023 | Variant summary: PFN1 c.350A>G (p.Glu117Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251482 control chromosomes. This frequency does not allow conclusions about variant significance. c.350A>G has been reported in the literature in individuals affected with PFN1-Related Disorders such as familial and sporadic Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and in unaffected controls with a reported moderate risk of association and a 95% CI that slightly overlaps 1 (example, PMID: 24309268). These report(s) do not provide unequivocal conclusions about an inherited penetrant association of the variant with PFN1-Related Disorders. Experimental evidence demonstrating an impact on protein function have suggested conflicting mechanism of action, namely gain of function due to TDP43 accumulation and loss of function due to altered stress granule dynamics (example, PMID: 26908597). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Amyotrophic lateral sclerosis type 18 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 23, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at