17-4948352-C-G

Variant names:

• chr17-4948352-C-G
• NM_005022.4:c.43G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005022.4(PFN1):​c.43G>C​(p.Gly15Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61

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]

ENO3 (HGNC:3354): (enolase 3) This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme is found in skeletal muscle cells in the adult where it may play a role in muscle development and regeneration. A switch from alpha enolase to beta enolase occurs in muscle tissue during development in rodents. Mutations in this gene have be associated glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN1	NM_005022.4	c.43G>C	p.Gly15Arg	missense_variant	Exon 1 of 3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.43G>C	p.Gly15Arg	missense_variant	Exon 1 of 2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFN1	ENST00000225655.6	c.43G>C	p.Gly15Arg	missense_variant	Exon 1 of 3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000572383.1	c.280G>C	p.Gly94Arg	missense_variant	Exon 2 of 3	3		ENSP00000460363.1
ENO3	ENST00000520221	c.-24C>G		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000467444.1
ENO3	ENST00000519266.5	c.-3+5C>G		splice_region_variant, intron_variant	Intron 1 of 1	3		ENSP00000467270.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458520 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Benign	0.13
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.60
Sift	Benign	0.11	T;.
Sift4G	Benign	0.74	T;.
Polyphen		0.96	P;.
Vest4		0.26
MutPred		0.40		Gain of solvent accessibility (P = 0.019);.;
MVP		0.90
MPC		1.6
ClinPred		0.95	D
GERP RS		2.2
Varity_R		0.54
gMVP		0.84

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: chr17-4851647;