10-116871222-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242699.2(ENO4):c.1145A>G(p.Asn382Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ENO4 NM_001242699.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16620314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENO4	NM_001242699.2	c.1145A>G	p.Asn382Ser	missense_variant	9/14	ENST00000341276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENO4	ENST00000341276.11	c.1145A>G	p.Asn382Ser	missense_variant	9/14	5	NM_001242699.2	P1
ENO4	ENST00000409522.5	c.320A>G	p.Asn107Ser	missense_variant	3/7	1
ENO4	ENST00000369207.3	c.617A>G	p.Asn206Ser	missense_variant	6/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398230 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689640

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

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

Jan 03, 2024

The c.1145A>G (p.N382S) alteration is located in exon 9 (coding exon 9) of the ENO4 gene. This alteration results from a A to G substitution at nucleotide position 1145, causing the asparagine (N) at amino acid position 382 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	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	15
Dann	Benign	0.95
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T;T;.;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;.;.;N
REVEL	Benign	0.15
Sift	Benign	0.10	T;.;.;T
Sift4G	Benign	0.064	T;T;T;T
Polyphen		0.28	B;.;.;.
Vest4		0.12
MVP		0.30
ClinPred		0.38	T
GERP RS		3.6
Varity_R		0.19
gMVP		0.25

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: rs1846687443; hg19: chr10-118630733;