NM_053013.4:c.1235+3A>G

Variant names:

• chr17-4956892-A-G
• rs73973669
• NM_053013.4:c.1235+3A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_053013.4(ENO3):​c.1235+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00288 in 1,614,224 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (46 hom.)
• Consequence: ENO3 NM_053013.4 splice_region, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.04
• Publications: 2 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]

ENO3 Gene-Disease associations (from GenCC):

• glycogen storage disease due to muscle beta-enolase deficiency

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 17-4956892-A-G is Benign according to our data. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4956892-A-G is described in CliVar as Benign. Clinvar id is 324152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.015 (2278/152332) while in subpopulation AFR AF = 0.0515 (2142/41566). AF 95% confidence interval is 0.0497. There are 56 homozygotes in GnomAd4. There are 1010 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENO3	NM_053013.4	c.1235+3A>G		splice_region_variant, intron_variant	Intron 11 of 11	ENST00000519602.6	NP_443739.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENO3	ENST00000519602.6	c.1235+3A>G		splice_region_variant, intron_variant	Intron 11 of 11	2	NM_053013.4	ENSP00000430055.2

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2275 AN: 152214 Hom.: 56 Cov.: 31

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00401 AC: 1009 AN: 251492 AF XY: 0.00293

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00162 AC: 2364 AN: 1461892 Hom.: 46 Cov.: 33 AF XY: 0.00141 AC XY: 1022 AN XY: 727248

African (AFR) AF: 0.0518 AC: 1734 AN: 33480

American (AMR) AF: 0.00367 AC: 164 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1112010

Other (OTH) AF: 0.00399 AC: 241 AN: 60396

GnomAD4 genome AF: 0.0150 AC: 2278 AN: 152332 Hom.: 56 Cov.: 31 AF XY: 0.0136 AC XY: 1010 AN XY: 74496

African (AFR) AF: 0.0515 AC: 2142 AN: 41566

American (AMR) AF: 0.00667 AC: 102 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00931 Hom.: 12

Bravo AF: 0.0175

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to muscle beta-enolase deficiency Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.86
PhyloP100		4.0
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.010		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: rs73973669; hg19: chr17-4860187;