17-4945989-G-C

Variant names:

• chr17-4945989-G-C
• rs13204
• NM_005022.4:c.334C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005022.4(PFN1):​c.334C>G​(p.Leu112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L112L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_005022.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22207117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN1	NM_005022.4	c.334C>G	p.Leu112Val	missense_variant	Exon 3 of 3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.*418C>G		3_prime_UTR_variant	Exon 2 of 2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFN1	ENST00000225655.6	c.334C>G	p.Leu112Val	missense_variant	Exon 3 of 3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000574872.1	c.226C>G	p.Leu76Val	missense_variant	Exon 2 of 2	2		ENSP00000465019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.65	N;.
PhyloP100		-0.017
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.20
Sift	Benign	0.55	T;.
Sift4G	Benign	0.69	T;T
Polyphen		0.013	B;.
Vest4		0.12
MutPred		0.38		Gain of ubiquitination at K116 (P = 0.0954);.;
MVP		0.74
MPC		2.6
ClinPred		0.17	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13204; hg19: chr17-4849284;