chr17-4945973-T-C

Position:

chr17-4945973-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

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 (★★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

PFN1
NM_005022.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 6.57

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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

BP4

Computational evidence support a benign effect (MetaRNN=0.14753288).

BS2

High AC in GnomAd4 at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4 linkuse as main transcript	c.350A>G	p.Glu117Gly	missense_variant	3/3	ENST00000225655.6	NP_005013.1	P07737
PFN1	NM_001375991.1 linkuse as main transcript	c.*434A>G		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 linkuse as main transcript	c.350A>G	p.Glu117Gly	missense_variant	3/3	1	NM_005022.4	ENSP00000225655.5		P07737
PFN1	ENST00000574872.1 linkuse as main transcript	c.242A>G	p.Glu81Gly	missense_variant	2/2	2		ENSP00000465019.1		K7EJ44

Frequencies

GnomAD3 genomes

AF:

0.000566

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000544

AC XY:

AN XY:

135918

show subpopulations

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.:

Cov.:

AF XY:

0.00108

AC XY:

786

AN XY:

726870

show subpopulations

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:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74400

show subpopulations

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.:

Bravo

AF:

0.000589

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.15

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.15

T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.65

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over