chr17-4948352-C-G

Variant names:

• chr17-4948352-C-G
• rs775379304
• NM_005022.4:c.43G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

• 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
• Publications: 0 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]

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]

ENO3 Gene-Disease associations (from GenCC):

• glycogen storage disease due to muscle beta-enolase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFN1	NM_005022.4	MANE Select	c.43G>C	p.Gly15Arg	missense	Exon 1 of 3	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.43G>C	p.Gly15Arg	missense	Exon 1 of 2	NP_001362920.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFN1	ENST00000225655.6	TSL:1 MANE Select	c.43G>C	p.Gly15Arg	missense	Exon 1 of 3	ENSP00000225655.5	P07737
	PFN1	ENST00000572383.1	TSL:3	c.280G>C	p.Gly94Arg	missense	Exon 2 of 3	ENSP00000460363.1	I3L3D5
	PFN1	ENST00000896490.1		c.43G>C	p.Gly15Arg	missense	Exon 2 of 4	ENSP00000566549.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32906

American (AMR) AF: 0.00 AC: 0 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39106

South Asian (SAS) AF: 0.00 AC: 0 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111108

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.13
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.6
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
PromoterAI		-0.0038	Neutral
Varity_R		0.54
gMVP		0.84
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs775379304; hg19: chr17-4851647;