17-4945982-A-G

Position:

• chr17-4945982-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 10 ACMG points.

• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 17-4945982-A-G is Pathogenic according to our data. Variant chr17-4945982-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 37035.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-4945982-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4	c.341T>C	p.Met114Thr	missense_variant	3/3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.*425T>C		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.341T>C	p.Met114Thr	missense_variant	3/3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000574872.1	c.233T>C	p.Met78Thr	missense_variant	2/2	2		ENSP00000465019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

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

Labcorp Genetics (formerly Invitae), Labcorp

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). -

PFN1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

The PFN1 c.341T>C variant is predicted to result in the amino acid substitution p.Met114Thr. This variant was reported in an individual(s) with amyotrophic lateral sclerosis (Wu et al. 2012. PubMed ID: 22801503; Corcia et al. 2021. PubMed ID: 33408239). In vitro assays showed p.Met114Thr promotes the formation of PFN1 aggregates and impacts its function (Tanaka et al. 2016. PubMed ID: 26908597). An in vivo fruit fly model suggested the variant may exert a loss-of-function mechanism (Wu et al. 2017. PubMed ID: 28379367) though other studies have suggested a gain-of-function mechanism via formin-induced actin polymerization ultimately resulting in neurodegeneration (Schmidt et al. 2021. PubMed ID: 34074767; Liu et al. 2022. PubMed ID: 35248815) This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.9	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.80		Loss of stability (P = 0.1116);.;
MVP		0.96
MPC		2.7
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907265; hg19: chr17-4849277;