17-4951185-C-T

Variant names:

• chr17-4951185-C-T
• rs366577
• NM_053013.4:c.-3+3C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053013.4(ENO3):​c.-3+3C>T variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_053013.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001005
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.644
• Publications: 14 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053013.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENO3	NM_053013.4	MANE Select	c.-3+3C>T		splice_region intron	N/A	NP_443739.3
	ENO3	NM_001374523.1		c.-32C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001361452.1
	ENO3	NM_001976.5		c.-42C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001967.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENO3	ENST00000519602.6	TSL:2 MANE Select	c.-3+3C>T		splice_region intron	N/A	ENSP00000430055.2
	ENO3	ENST00000521659.5	TSL:1	n.-3+3C>T		splice_region intron	N/A	ENSP00000430554.1
	ENO3	ENST00000323997.10	TSL:5	c.-42C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000324105.6

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

African (AFR) AF: 0.249 AC: 3941 AN: 15802

American (AMR) AF: 0.436 AC: 839 AN: 1924

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 2748 AN: 5166

East Asian (EAS) AF: 0.154 AC: 579 AN: 3748

South Asian (SAS) AF: 0.363 AC: 6156 AN: 16954

European-Finnish (FIN) AF: 0.513 AC: 159 AN: 310

Middle Eastern (MID) AF: 0.442 AC: 717 AN: 1622

European-Non Finnish (NFE) AF: 0.594 AC: 453711 AN: 764132

Other (OTH) AF: 0.522 AC: 14318 AN: 27430

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

African (AFR) AF: 0.274 AC: 11356 AN: 41400

American (AMR) AF: 0.450 AC: 6860 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1793 AN: 3472

East Asian (EAS) AF: 0.146 AC: 753 AN: 5164

South Asian (SAS) AF: 0.345 AC: 1660 AN: 4818

European-Finnish (FIN) AF: 0.476 AC: 5009 AN: 10514

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.583 AC: 39578 AN: 67940

Other (OTH) AF: 0.498 AC: 1047 AN: 2104

Alfa AF: 0.389 Hom.: 1253

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

Dec 02, 2015

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.

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

Jan 13, 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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.62
PhyloP100		0.64
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs366577; hg19: chr17-4854480;