17-4948321-TA-AG

Position:

• chr17-4948321-TA-AG

Variant summary

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

The ENST00000225655.6(PFN1):​c.73_74delinsCT​(p.Tyr25Leu) 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: 33)
• Consequence: PFN1 ENST00000225655.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

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 1 benign (90%) in ENST00000225655.6
• 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.73_74delinsCT	p.Tyr25Leu	missense_variant	1/3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.73_74delinsCT	p.Tyr25Leu	missense_variant	1/2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFN1	ENST00000225655.6	c.73_74delinsCT	p.Tyr25Leu	missense_variant	1/3	1	NM_005022.4	ENSP00000225655	P1
PFN1	ENST00000572383.1	c.310_311delinsCT	p.Tyr104Leu	missense_variant	2/3	3		ENSP00000460363
ENO3	ENST00000519266.5	c.-29_-28delinsAG		5_prime_UTR_variant	1/2	3		ENSP00000467270
ENO3	ENST00000520221.5	c.-55_-54delinsAG		5_prime_UTR_variant	1/7	5		ENSP00000467444

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 10, 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals with PFN1-related conditions. The frequency data for this variant in the population databases is not available, as this variant may be reported as separate entries in the ExAC database. This sequence change replaces tyrosine with leucine at codon 25 of the PFN1 protein (p.Tyr25Leu). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and leucine. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr17-4851616;