NM_005022.4:c.350_351delAAinsGT

Variant names:

• chr17-4945972-TT-AC
• rs1597686012
• NM_005022.4:c.350_351delAAinsGT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1 PM1 PM2

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 the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• 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]

ACMG classification

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 rank	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	Exon 2 of 2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Jul 30, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22801503, 25943890, 23634771, 23063648, 26226631, 25499087, 23312802, 23141414) -

not specified Uncertain:2

Mar 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 11, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1597686012; hg19: chr17-4849267;