10-116860859-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001242699.2(ENO4):c.700G>A(p.Gly234Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ENO4 NM_001242699.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

ENO4 (HGNC:31670): (enolase 4) Predicted to enable phosphopyruvate hydratase activity. Predicted to be involved in glycolytic process and regulation of vacuole fusion, non-autophagic. Predicted to act upstream of or within cilium organization and flagellated sperm motility. Predicted to be located in sperm principal piece. Predicted to be part of phosphopyruvate hydratase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENO4	NM_001242699.2	c.700G>A	p.Gly234Ser	missense_variant	5/14	ENST00000341276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENO4	ENST00000341276.11	c.700G>A	p.Gly234Ser	missense_variant	5/14	5	NM_001242699.2	P1
ENO4	ENST00000409522.5	c.166-7791G>A		intron_variant		1
ENO4	ENST00000369207.3	c.172G>A	p.Gly58Ser	missense_variant	2/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396940 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 688892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.700G>A (p.G234S) alteration is located in exon 5 (coding exon 5) of the ENO4 gene. This alteration results from a G to A substitution at nucleotide position 700, causing the glycine (G) at amino acid position 234 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
REVEL	Pathogenic	0.75
Sift4G	Pathogenic	0.0	D;D
Vest4		0.75
MVP		0.099
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.40
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs1846390265; hg19: chr10-118620370;