chr17-4945972-TT-AC
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1PM1PM2
The NM_005022.4(PFN1):c.350_351delAAinsGT(p.Glu117Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.
Frequency
Genomes: not found (cov: 32)
Consequence
PFN1
NM_005022.4 missense
NM_005022.4 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.57
Genes affected
PFN1 (HGNC:8881): (profilin 1) This gene encodes a member of the profilin family of small actin-binding proteins. The encoded protein plays an important role in actin dynamics by regulating actin polymerization in response to extracellular signals. Deletion of this gene is associated with Miller-Dieker syndrome, and the encoded protein may also play a role in Huntington disease. Multiple pseudogenes of this gene are located on chromosome 1. [provided by RefSeq, Jul 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PS1
Transcript NM_005022.4 (PFN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
In a chain Profilin-1 (size 138) in uniprot entity PROF1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005022.4
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PFN1 | NM_005022.4 | c.350_351delAAinsGT | p.Glu117Gly | missense_variant | ENST00000225655.6 | NP_005013.1 | ||
PFN1 | NM_001375991.1 | c.*434_*435delAAinsGT | 3_prime_UTR_variant | 2/2 | NP_001362920.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PFN1 | ENST00000225655.6 | c.350_351delAAinsGT | p.Glu117Gly | missense_variant | 1 | NM_005022.4 | ENSP00000225655.5 | |||
PFN1 | ENST00000574872.1 | c.242_243delAAinsGT | p.Glu81Gly | missense_variant | 2 | ENSP00000465019.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2020 | This variant is associated with the following publications: (PMID: 22801503, 25943890, 23634771, 23063648, 26226631, 25499087, 23312802, 23141414) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 117 of the PFN1 protein (p.Glu117Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD) (PMID: 22801503, 23063648, 23141414, 23312802, 23634771, 23635659, 24309268, 25943890). ClinVar contains an entry for this variant (Variation ID: 646360). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PFN1 function (PMID: 22801503, 24920614, 26056300, 27432186, 28040732, 35628504). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 30, 2019 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 10, 2023 | Variant summary: PFN1 c.350_351delinsGT (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 0.00048 in 282822 control chromosomes (gnomAD). This frequency does not allow any conclusion about variant significance. c.350_351delinsGT has been reported in the literature in individuals affected with PFN1-Related Disorders (example: Wu_2012, Tiloca_2013, Ingre_2013, Dillen_2013, vanBlitterswijk_2013, Yang_2013, Pottier_2015, Fratta_2013, and Smith_2015) as well as study control subjects (example: Wu_2012, Dillen_2013, van Blitterswijk_2013, Fratta_2013, Smith_2015). In at-least, one of these individuals a pathogenic co-occurrence on GRN (p.A303GfsX14) was reported (Dillen_2013). Multiple reports have provided experimental evidence evaluating an impact on protein function. While some studies showed no damaging effect of this variant (example: Wu_2012, and Figley_ 2014) few others suggest this variant could be a risk factor for disease (example: Boopathy_2014 and Tanaka_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after and classified the variant as VUS (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at