Genetic Variant NM_005022.4:c.35T>C (chr17-4948360-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_005022.4(PFN1):c.35T>C(p.Met12Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PFN1
NM_005022.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.35

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:

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]

ENO3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN1	NM_005022.4 link	c.35T>C	p.Met12Thr	missense_variant	Exon 1 of 3	ENST00000225655.6	NP_005013.1	P07737
PFN1	NM_001375991.1 link	c.35T>C	p.Met12Thr	missense_variant	Exon 1 of 2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PFN1	ENST00000225655.6 link	c.35T>C	p.Met12Thr	missense_variant	Exon 1 of 3	1	NM_005022.4	ENSP00000225655.5	P07737
PFN1	ENST00000572383.1 link	c.272T>C	p.Met91Thr	missense_variant	Exon 2 of 3	3		ENSP00000460363.1	I3L3D5
ENO3	ENST00000520221 link	c.-16A>G		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000467444.1	K7EPM1
ENO3	ENST00000519266.5 link	c.-3+13A>G		intron_variant	Intron 1 of 1	3		ENSP00000467270.1	K7EP84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725434

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35T>C (p.M12T) alteration is located in exon 1 (coding exon 1) of the PFN1 gene. This alteration results from a T to C substitution at nucleotide position 35, causing the methionine (M) at amino acid position 12 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Pathogenic

0.85

D;D

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

-0.00060

MutationAssessor

Benign

1.8

L;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.1

N;.

REVEL

Pathogenic

0.65

Sift

Benign

0.28

T;.

Sift4G

Benign

0.14

T;.

Polyphen

0.23

B;.

Vest4

0.60

MutPred

0.48

Loss of stability (P = 0.0517);.;

MVP

0.91

MPC

1.6

ClinPred

0.92

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.90

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over