17-4948306-G-T

Variant names:

• chr17-4948306-G-T
• NM_005022.4:c.89C>A

Variant summary

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

The NM_005022.4(PFN1):​c.89C>A​(p.Ser30Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S30S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

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]

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 4 ACMG points.

• PM1: In a chain Profilin-1 (size 138) in uniprot entity PROF1_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) 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.89C>A	p.Ser30Tyr	missense_variant	Exon 1 of 3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.89C>A	p.Ser30Tyr	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.89C>A	p.Ser30Tyr	missense_variant	Exon 1 of 3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000572383.1	c.326C>A	p.Ser109Tyr	missense_variant	Exon 2 of 3	3		ENSP00000460363.1
ENO3	ENST00000520221	c.-70G>T		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000467444.1
ENO3	ENST00000519266	c.-44G>T		5_prime_UTR_variant	Exon 1 of 2	3		ENSP00000467270.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89C>A (p.S30Y) alteration is located in exon 1 (coding exon 1) of the PFN1 gene. This alteration results from a C to A substitution at nucleotide position 89, causing the serine (S) at amino acid position 30 to be replaced by a tyrosine (Y). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.43	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.088	T;.
Sift4G	Benign	0.72	T;.
Polyphen		0.027	B;.
Vest4		0.19
MutPred		0.62		Loss of disorder (P = 0.1114);.;
MVP		0.91
MPC		2.2
ClinPred		0.97	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.35
gMVP		0.90

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: chr17-4851601;