ENST00000520221.5:c.-3+191delC

Variant names:

• chr17-4948563-TC-T
• rs376068871
• ENST00000896245.1:c.-3+200delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000520221.5(ENO3):​c.-3+191delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 421,292 control chromosomes in the GnomAD database, including 2,629 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (730 hom., cov: 28)
  • Exomes 𝑓: 0.18 (1899 hom.)
• Consequence: ENO3 ENST00000520221.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.31
• Publications: 1 publications found

Genes affected

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]

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]

PFN1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 17-4948563-TC-T is Benign according to our data. Variant chr17-4948563-TC-T is described in ClinVar as Benign. ClinVar VariationId is 1228307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000520221.5. 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.-170delG		upstream_gene	N/A	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-170delG		upstream_gene	N/A	NP_001362920.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENO3	ENST00000896245.1		c.-3+200delC		intron	N/A	ENSP00000566304.1
	ENO3	ENST00000520221.5	TSL:5	c.-3+191delC		intron	N/A	ENSP00000467444.1	K7EPM1
	PFN1	ENST00000572383.1	TSL:3	c.77-9delG		intron	N/A	ENSP00000460363.1	I3L3D5

Frequencies

GnomAD3 genomes AF: 0.105 AC: 12886 AN: 122284 Hom.: 729 Cov.: 28

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0536

Gnomad SAS AF: 0.0504

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.0919

GnomAD2 exomes AF: 0.376 AC: 350 AN: 932 AF XY: 0.378

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.185 AC: 55234 AN: 298980 Hom.: 1899 Cov.: 3 AF XY: 0.184 AC XY: 28271 AN XY: 153298

African (AFR) AF: 0.101 AC: 579 AN: 5734

American (AMR) AF: 0.133 AC: 731 AN: 5502

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 1371 AN: 7478

East Asian (EAS) AF: 0.0934 AC: 1594 AN: 17068

South Asian (SAS) AF: 0.147 AC: 2771 AN: 18806

European-Finnish (FIN) AF: 0.270 AC: 5136 AN: 19038

Middle Eastern (MID) AF: 0.152 AC: 187 AN: 1234

European-Non Finnish (NFE) AF: 0.192 AC: 39921 AN: 208142

Other (OTH) AF: 0.184 AC: 2944 AN: 15978

GnomAD4 genome AF: 0.105 AC: 12888 AN: 122312 Hom.: 730 Cov.: 28 AF XY: 0.107 AC XY: 6340 AN XY: 59184

African (AFR) AF: 0.0397 AC: 1237 AN: 31124

American (AMR) AF: 0.0778 AC: 952 AN: 12230

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 306 AN: 2972

East Asian (EAS) AF: 0.0538 AC: 224 AN: 4166

South Asian (SAS) AF: 0.0512 AC: 188 AN: 3670

European-Finnish (FIN) AF: 0.229 AC: 1770 AN: 7720

Middle Eastern (MID) AF: 0.118 AC: 27 AN: 228

European-Non Finnish (NFE) AF: 0.137 AC: 7911 AN: 57780

Other (OTH) AF: 0.0915 AC: 148 AN: 1618

Alfa AF: 0.0413 Hom.: 36

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=299/1	polymorphism (auto)

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: rs376068871; hg19: chr17-4851858; COSMIC: COSV52590924; COSMIC: COSV52590924;