17-4951185-C-T

Position:

• chr17-4951185-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001976.5(ENO3):​c.-42C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 988,960 control chromosomes in the GnomAD database, including 158,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17150 hom., cov: 31)
  • Exomes 𝑓: 0.58 (141507 hom.)
• Consequence: ENO3 NM_001976.5 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00001005
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.644

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 17-4951185-C-T is Benign according to our data. Variant chr17-4951185-C-T is described in ClinVar as [Benign]. Clinvar id is 324134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENO3	NM_053013.4	c.-3+3C>T		splice_region_variant, intron_variant		ENST00000519602.6	NP_443739.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENO3	ENST00000519602.6	c.-3+3C>T		splice_region_variant, intron_variant		2	NM_053013.4	ENSP00000430055.2

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68656 AN: 151754 Hom.: 17139 Cov.: 31

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.496

GnomAD4 exome AF: 0.577 AC: 483168 AN: 837088 Hom.: 141507 Cov.: 33 AF XY: 0.577 AC XY: 223201 AN XY: 386876

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.436

Gnomad4 ASJ exome AF: 0.532

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.513

Gnomad4 NFE exome AF: 0.594

Gnomad4 OTH exome AF: 0.522

GnomAD4 genome AF: 0.452 AC: 68697 AN: 151872 Hom.: 17150 Cov.: 31 AF XY: 0.443 AC XY: 32871 AN XY: 74178

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.476

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.498

Alfa AF: 0.397 Hom.: 1216

Bravo AF: 0.444

Asia WGS AF: 0.269 AC: 936 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Glycogen storage disease due to muscle beta-enolase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs366577; hg19: chr17-4854480;