Genetic Variant PFN4:p.Val90Met (chr2-24119670-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_199346.3(PFN4):c.268G>A(p.Val90Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,610,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PFN4
NM_199346.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.871

Variant links:

Genes affected

PFN4 (HGNC:31103): (profilin family member 4) Predicted to enable actin monomer binding activity. Predicted to be involved in sequestering of actin monomers. Predicted to be located in cytoskeleton. Predicted to be active in cell cortex. [provided by Alliance of Genome Resources, Apr 2022]

PFN4 links:

FAM228B (HGNC:24736): (family with sequence similarity 228 member B)

FAM228B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN4	NM_199346.3 link	c.268G>A	p.Val90Met	missense_variant	Exon 4 of 5	ENST00000313213.5	NP_955378.1	Q8NHR9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PFN4	ENST00000313213.5 link	c.268G>A	p.Val90Met	missense_variant	Exon 4 of 5	1	NM_199346.3	ENSP00000322170.4	Q8NHR9
FAM228B	ENST00000613899.4 link	c.-120-15449C>T		intron_variant	Intron 3 of 10	1		ENSP00000479742.1	A0A087WVX1
PFN4	ENST00000465360.1 link	n.353G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2
FAM228B	ENST00000486967.5 link	n.123-15449C>T		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250662

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000174

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458096

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725550

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

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

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268G>A (p.V90M) alteration is located in exon 4 (coding exon 3) of the PFN4 gene. This alteration results from a G to A substitution at nucleotide position 268, causing the valine (V) at amino acid position 90 to be replaced by a methionine (M). 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

Benign

0.14

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.85

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.51

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.50

Sift

Benign

0.14

Sift4G

Benign

0.16

Polyphen

0.45

Vest4

0.51

MVP

0.75

MPC

0.064

ClinPred

0.12

GERP RS

4.5

Varity_R

0.077

gMVP

0.43

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