17-4948352-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The ENST00000225655.6(PFN1):​c.43G>A​(p.Gly15Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,610,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PFN1
ENST00000225655.6 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61
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]
ENO3 (HGNC:3354): (enolase 3) This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme is found in skeletal muscle cells in the adult where it may play a role in muscle development and regeneration. A switch from alpha enolase to beta enolase occurs in muscle tissue during development in rodents. Mutations in this gene have be associated glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jul 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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 ENST00000225655.6
BS2
High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PFN1NM_005022.4 linkuse as main transcriptc.43G>A p.Gly15Arg missense_variant 1/3 ENST00000225655.6 NP_005013.1
PFN1NM_001375991.1 linkuse as main transcriptc.43G>A p.Gly15Arg missense_variant 1/2 NP_001362920.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PFN1ENST00000225655.6 linkuse as main transcriptc.43G>A p.Gly15Arg missense_variant 1/31 NM_005022.4 ENSP00000225655 P1
PFN1ENST00000572383.1 linkuse as main transcriptc.280G>A p.Gly94Arg missense_variant 2/33 ENSP00000460363
ENO3ENST00000520221.5 linkuse as main transcriptc.-24C>T 5_prime_UTR_variant 1/75 ENSP00000467444
ENO3ENST00000519266.5 linkuse as main transcriptc.-3+5C>T splice_donor_5th_base_variant, intron_variant 3 ENSP00000467270

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000122
AC:
3
AN:
245740
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
133574
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000897
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1458520
Hom.:
0
Cov.:
34
AF XY:
0.0000124
AC XY:
9
AN XY:
725726
show subpopulations
Gnomad4 AFR exome
AF:
0.0000304
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000313
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 29, 2023This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 15 of the PFN1 protein (p.Gly15Arg). This variant is present in population databases (rs775379304, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PFN1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.067
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
D;D
Eigen
Benign
0.098
Eigen_PC
Benign
0.061
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Uncertain
0.69
D;D
MetaSVM
Uncertain
-0.011
T
MutationAssessor
Uncertain
2.6
M;.
MutationTaster
Benign
0.99
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.4
D;.
REVEL
Uncertain
0.57
Sift
Benign
0.11
T;.
Sift4G
Benign
0.74
T;.
Polyphen
0.98
D;.
Vest4
0.26
MutPred
0.40
Gain of solvent accessibility (P = 0.019);.;
MVP
0.89
MPC
1.6
ClinPred
0.47
T
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.54
gMVP
0.84

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.

Other links and lift over

dbSNP: rs775379304; hg19: chr17-4851647; API