dbSNP rs370808524: PFN4:p.Val90Leu (chr2-24119670-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_199346.3(PFN4):c.268G>T(p.Val90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V90M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PFN4
NM_199346.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2592349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN4	NM_199346.3 link	c.268G>T	p.Val90Leu	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>T	p.Val90Leu	missense_variant	Exon 4 of 5	1	NM_199346.3	ENSP00000322170.4	Q8NHR9
FAM228B	ENST00000613899.4 link	c.-120-15449C>A		intron_variant	Intron 3 of 10	1		ENSP00000479742.1	A0A087WVX1
PFN4	ENST00000465360.1 link	n.353G>T		non_coding_transcript_exon_variant	Exon 3 of 4	2
FAM228B	ENST00000486967.5 link	n.123-15449C>A		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152186

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.0000199

AC:

AN:

250662

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

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:

0.00000206

AC:

AN:

1458096

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Benign

6.3

DANN

Benign

0.75

DEOGEN2

Benign

0.34

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.73

M_CAP

Benign

0.027

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.67

REVEL

Uncertain

0.30

Sift

Benign

0.61

Sift4G

Benign

0.91

Polyphen

0.0020

Vest4

0.19

MutPred

0.73

Loss of methylation at K94 (P = 0.0899);

MVP

0.65

MPC

0.056

ClinPred

0.021

GERP RS

4.5

Varity_R

0.092

gMVP

0.38

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over