rs387907266

Variant names:

• chr17-4945970-C-A
• rs387907266
• NM_005022.4:c.353G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-4945970-C-A
• chr17-4945970-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005022.4(PFN1):​c.353G>T​(p.Gly118Val) variant causes a missense change. 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. G118S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.48
• Publications: 70 publications found

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]

PFN1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 17-4945970-C-A is Pathogenic according to our data. Variant chr17-4945970-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37036.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN1	NM_005022.4	c.353G>T	p.Gly118Val	missense_variant	Exon 3 of 3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.*437G>T		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.353G>T	p.Gly118Val	missense_variant	Exon 3 of 3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000574872.1	c.245G>T	p.Gly82Val	missense_variant	Exon 2 of 2	2		ENSP00000465019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251482 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 18 Pathogenic:1

Aug 23, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 118 of the PFN1 protein (p.Gly118Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 22801503, 31401564, 31802421). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37036). 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 have shown that this missense change affects PFN1 function (PMID: 22801503, 26226631, 26908597). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.9	M;.
PhyloP100		6.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.2	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.69		Gain of ubiquitination at K116 (P = 0.0828);.;
MVP		0.97
MPC		2.8
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.98
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs387907266; hg19: chr17-4849265;