17-4945908-G-C

Position:

• chr17-4945908-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005022.4(PFN1):​c.415C>G​(p.Gln139Glu) 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. 13/21 in silico tools predict a benign outcome for this variant. 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, single submitter U:1
• Conservation: PhyloP100: 1.48

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.21211898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4	c.415C>G	p.Gln139Glu	missense_variant	3/3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.*499C>G		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.415C>G	p.Gln139Glu	missense_variant	3/3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000574872.1	c.307C>G	p.Gln103Glu	missense_variant	2/2	2		ENSP00000465019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.415C>G (p.Q139E) alteration is located in exon 3 (coding exon 3) of the PFN1 gene. This alteration results from a C to G substitution at nucleotide position 415, causing the glutamine (Q) at amino acid position 139 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.65	N;.
REVEL	Uncertain	0.45
Sift	Benign	0.059	T;.
Sift4G	Benign	0.088	T;T
Polyphen		0.074	B;.
Vest4		0.17
MutPred		0.44		Loss of MoRF binding (P = 0.0067);.;
MVP		0.81
MPC		1.5
ClinPred		0.12	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4849203;