17-4945922-T-G

Position:

• chr17-4945922-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005022.4(PFN1):​c.401A>C​(p.His134Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.46

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Profilin-1 (size 138) in uniprot entity PROF1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005022.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4	c.401A>C	p.His134Pro	missense_variant	3/3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.*485A>C		3_prime_UTR_variant	2/2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFN1	ENST00000225655.6	c.401A>C	p.His134Pro	missense_variant	3/3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000574872.1	c.293A>C	p.His98Pro	missense_variant	2/2	2		ENSP00000465019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 28, 2021	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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PFN1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with proline at codon 134 of the PFN1 protein (p.His134Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2019	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.89
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.25	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Uncertain	0.50
Sift	Benign	0.048	D;.
Sift4G	Benign	0.063	T;T
Polyphen		0.66	P;.
Vest4		0.55
MutPred		0.71		Gain of glycosylation at H134 (P = 0.0342);.;
MVP		0.79
MPC		3.0
ClinPred		0.93	D
GERP RS		1.8
Varity_R		0.92
gMVP		1.0

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: rs1050184; hg19: chr17-4849217;