17-4945972-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1 PM5 BP4_Moderate BP6_Moderate BS2

The NM_005022.4(PFN1):c.351A>T(p.Glu117Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,184 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E117G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.914

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_benign. Variant got -4 ACMG points.

• PM1: In a chain Profilin-1 (size 138) in uniprot entity PROF1_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_005022.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-4945973-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.08447835).
• BP6: Variant 17-4945972-T-A is Benign according to our data. Variant chr17-4945972-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1806047.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFN1	NM_005022.4	c.351A>T	p.Glu117Asp	missense_variant	3/3	ENST00000225655.6
PFN1	NM_001375991.1	c.*435A>T		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFN1	ENST00000225655.6	c.351A>T	p.Glu117Asp	missense_variant	3/3	1	NM_005022.4	P1
PFN1	ENST00000574872.1	c.243A>T	p.Glu81Asp	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000481 AC: 121 AN: 251480 Hom.: 0 AF XY: 0.000530 AC XY: 72 AN XY: 135916

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000993

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00114 AC: 1665 AN: 1460982 Hom.: 1 Cov.: 29 AF XY: 0.00107 AC XY: 781 AN XY: 726858

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74406

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 18 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous in-frame deletion insertion variant was identified, NM_005022.3(PFN1):c.350_351delinsGT in exon 3 of 3 of the PFN1 gene. This in-frame deletion insertion is predicted to create a moderate amino acid change from a glutamic acid to a glycine at position 117 of the protein, NP_005013.1(PFN1):p.(Glu117Gly). The glutamic acid at this position has high conservation (100 vertebrates, UCSC) and is located within the profiling domain. This variant is seen in gnomAD as two independent missense variants at a frequency of 0.05% each (140 heterozygotes and 136 heterozygotes). The variant has been previously reported in patients with ALS and also in control populations. Recent publications have called this variant a risk factor (ClinVar, Wu, CH. et al. (2012), Yang, S. et al. (2013), Fratta, P. et al. (2014)). Additionally, conflicting functional evidence has been reported for this variant (Wu, CH. et al. (2012), Henty-Ridilla, JL. et al. (2018)). A different variant in the same codon resulting in a change to aspartic acid has also been reported as pathogenic in ALS (Yang, S. et al. (2013)). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D
Eigen	Benign	-0.069
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.084	T;T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.029	D;D
Polyphen		0.056	B;.
Vest4		0.28
MutPred		0.67		Loss of ubiquitination at K116 (P = 0.1351);.;
MVP		0.90
MPC		2.5
ClinPred		0.058	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs151313170; hg19: chr17-4849267;