chr17-4945972-T-A

Position:

chr17-4945972-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM5BP4_ModerateBP6_ModerateBS2

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 Pathogenic.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

PFN1
NM_005022.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.914

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

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 GnomAd4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4 linkuse as main transcript	c.351A>T	p.Glu117Asp	missense_variant	3/3	ENST00000225655.6	NP_005013.1	P07737
PFN1	NM_001375991.1 linkuse as main transcript	c.*435A>T		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.351A>T	p.Glu117Asp	missense_variant	3/3	1	NM_005022.4	ENSP00000225655.5		P07737
PFN1	ENST00000574872.1 linkuse as main transcript	c.243A>T	p.Glu81Asp	missense_variant	2/2	2		ENSP00000465019.1		K7EJ44

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000530

AC XY:

AN XY:

135916

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:

0.0000924

Gnomad NFE exome

AF:

0.000993

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00114

AC:

1665

AN:

1460982

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

781

AN XY:

726858

show subpopulations

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:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74406

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:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000893

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:

0.000404

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D

Eigen

Benign

-0.069

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.084

T;T

MetaSVM

Uncertain

0.026

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.69

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

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

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