17-4945954-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_005022.4(PFN1):c.369G>C(p.Leu123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0500

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 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 NM_005022.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0852364).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFN1	NM_005022.4	c.369G>C	p.Leu123Phe	missense_variant	3/3	ENST00000225655.6
PFN1	NM_001375991.1	c.*453G>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFN1	ENST00000225655.6	c.369G>C	p.Leu123Phe	missense_variant	3/3	1	NM_005022.4	P1
PFN1	ENST00000574872.1	c.261G>C	p.Leu87Phe	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461506 Hom.: 0 Cov.: 29 AF XY: 0.0000151 AC XY: 11 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00191

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2023

The c.369G>C (p.L123F) alteration is located in exon 3 (coding exon 3) of the PFN1 gene. This alteration results from a G to C substitution at nucleotide position 369, causing the leucine (L) at amino acid position 123 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 123 of the PFN1 protein (p.Leu123Phe). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1024397). This variant has not been reported in the literature in individuals affected with PFN1-related conditions. This variant is present in population databases (no rsID available, gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.13	T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.58	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.72	T;.
Sift4G	Benign	0.70	T;T
Polyphen		0.0	B;.
Vest4		0.077
MutPred		0.21		Gain of methylation at K127 (P = 0.0732);.;
MVP		0.58
MPC		1.4
ClinPred		0.063	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.85

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

Other links and lift over

dbSNP: rs1002369755; hg19: chr17-4849249;