NM_001242699.2:c.1745T>C

Variant names:

• chr10-116881536-T-C
• rs953823932
• NM_001242699.2:c.1745T>C

Variant summary

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

The NM_001242699.2(ENO4):​c.1745T>C​(p.Phe582Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,392,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: ENO4 NM_001242699.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

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]

SHTN1 (HGNC:29319): (shootin 1) Enables identical protein binding activity. Involved in positive regulation of neuron migration. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENO4	NM_001242699.2	c.1745T>C	p.Phe582Ser	missense_variant	Exon 14 of 14	ENST00000341276.11	NP_001229628.1
SHTN1	NM_001127211.3	c.*4808A>G		3_prime_UTR_variant	Exon 17 of 17	ENST00000355371.9	NP_001120683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENO4	ENST00000341276.11	c.1745T>C	p.Phe582Ser	missense_variant	Exon 14 of 14	5	NM_001242699.2	ENSP00000345555.6
SHTN1	ENST00000355371	c.*4808A>G		3_prime_UTR_variant	Exon 17 of 17	2	NM_001127211.3	ENSP00000347532.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000139 AC: 2 AN: 144174 Hom.: 0 AF XY: 0.0000257 AC XY: 2 AN XY: 77708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000973

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000503 AC: 7 AN: 1392698 Hom.: 0 Cov.: 30 AF XY: 0.00000582 AC XY: 4 AN XY: 686720

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: 0.00000557

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1745T>C (p.F582S) alteration is located in exon 14 (coding exon 14) of the ENO4 gene. This alteration results from a T to C substitution at nucleotide position 1745, causing the phenylalanine (F) at amino acid position 582 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	0.27
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	0.041
Eigen_PC	Benign	0.0031
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.65	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.64
MutPred		0.59		.;.;Gain of disorder (P = 0.0087);
MVP		0.55
ClinPred		0.49	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.47

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: rs953823932; hg19: chr10-118641047;