Genetic Variant PFN4:p.Gly107Ser (chr2-24119619-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_199346.3(PFN4):c.319G>A(p.Gly107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PFN4
NM_199346.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.410

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06919193).

BP6

Variant 2-24119619-C-T is Benign according to our data. Variant chr2-24119619-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3211610.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN4	NM_199346.3 link	c.319G>A	p.Gly107Ser	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.319G>A	p.Gly107Ser	missense_variant	Exon 4 of 5	1	NM_199346.3	ENSP00000322170.4	Q8NHR9
FAM228B	ENST00000613899.4 link	c.-120-15500C>T		intron_variant	Intron 3 of 10	1		ENSP00000479742.1	A0A087WVX1
PFN4	ENST00000465360.1 link	n.404G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2
FAM228B	ENST00000486967.5 link	n.123-15500C>T		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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

AF:

0.0000329

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

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

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 26, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.3

DANN

Benign

0.63

DEOGEN2

Benign

0.41

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.67

M_CAP

Benign

0.011

MetaRNN

Benign

0.069

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.61

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

REVEL

Benign

0.13

Sift

Benign

0.46

Sift4G

Benign

0.79

Polyphen

0.0010

Vest4

0.13

MutPred

0.45

Gain of catalytic residue at G107 (P = 0.0348);

MVP

0.38

MPC

0.058

ClinPred

0.027

GERP RS

1.2

Varity_R

0.041

gMVP

0.49

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