rs140547520

chr17-4945973-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_005022.4(PFN1):c.350A>G(p.Glu117Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,613,144 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E117D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• 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_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
• BP4: Computational evidence support a benign effect (MetaRNN=0.14753288).
• BS2: High AC in GnomAd at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFN1	NM_005022.4	c.350A>G	p.Glu117Gly	missense_variant	3/3	ENST00000225655.6
PFN1	NM_001375991.1	c.*434A>G		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFN1	ENST00000225655.6	c.350A>G	p.Glu117Gly	missense_variant	3/3	1	NM_005022.4	P1
PFN1	ENST00000574872.1	c.242A>G	p.Glu81Gly	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000566 AC: 86 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000497 AC: 125 AN: 251482 Hom.: 0 AF XY: 0.000544 AC XY: 74 AN XY: 135918

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: 0.000139

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00115 AC: 1673 AN: 1460978 Hom.: 1 Cov.: 29 AF XY: 0.00108 AC XY: 786 AN XY: 726870

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74400

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: 0.0000943

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000963 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: 0.000412 AC: 50

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2023	Variant summary: PFN1 c.350A>G (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 0.0005 in 251482 control chromosomes. This frequency does not allow conclusions about variant significance. c.350A>G has been reported in the literature in individuals affected with PFN1-Related Disorders such as familial and sporadic Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and in unaffected controls with a reported moderate risk of association and a 95% CI that slightly overlaps 1 (example, PMID: 24309268). These report(s) do not provide unequivocal conclusions about an inherited penetrant association of the variant with PFN1-Related Disorders. Experimental evidence demonstrating an impact on protein function have suggested conflicting mechanism of action, namely gain of function due to TDP43 accumulation and loss of function due to altered stress granule dynamics (example, PMID: 26908597). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Amyotrophic lateral sclerosis type 18 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 23, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		0.0050	B;.
Vest4		0.66
MVP		0.87
MPC		2.8
ClinPred		0.15	T
GERP RS		3.4
Varity_R		0.73
gMVP		0.97

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: rs140547520; hg19: chr17-4849268;