17-4955097-G-C

Variant names:

• chr17-4955097-G-C
• rs121918403
• NM_053013.4:c.467G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_053013.4(ENO3):​c.467G>C​(p.Gly156Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G156D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENO3 NM_053013.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 13 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-4955097-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16617.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

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.467G>C	p.Gly156Ala	missense	Exon 7 of 12	NP_443739.3
	ENO3	NM_001374524.1		c.494G>C	p.Gly165Ala	missense	Exon 7 of 12	NP_001361453.1
	ENO3	NM_001374523.1		c.467G>C	p.Gly156Ala	missense	Exon 7 of 12	NP_001361452.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENO3	ENST00000519602.6	TSL:2 MANE Select	c.467G>C	p.Gly156Ala	missense	Exon 7 of 12	ENSP00000430055.2
	ENO3	ENST00000518175.1	TSL:1	c.467G>C	p.Gly156Ala	missense	Exon 6 of 11	ENSP00000431087.1
	ENO3	ENST00000521659.5	TSL:1	n.*413G>C		non_coding_transcript_exon	Exon 8 of 9	ENSP00000430554.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251184 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.88	P
Vest4		0.96
MutPred		0.96		Loss of disorder (P = 0.128)
MVP		0.97
MPC		0.45
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.90

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: rs121918403; hg19: chr17-4858392;