17-4945989-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005022.4(PFN1):​c.334C>A​(p.Leu112Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN1	NM_005022.4	c.334C>A	p.Leu112Met	missense_variant	Exon 3 of 3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.*418C>A		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>A	p.Leu112Met	missense_variant	Exon 3 of 3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000574872.1	c.226C>A	p.Leu76Met	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	0.26
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.3	L;.
PhyloP100		-0.017
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.85	N;.
REVEL	Uncertain	0.47
Sift	Benign	0.12	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.98	D;.
Vest4		0.35
MutPred		0.46		Gain of sheet (P = 0.0344);.;
MVP		0.84
MPC		2.5
ClinPred		0.77	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.96

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;