3-36991520-A-G

Variant names:

• chr3-36991520-A-G
• NM_014805.4:c.1558T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014805.4(EPM2AIP1):​c.1558T>C​(p.Tyr520His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPM2AIP1 NM_014805.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56
• Publications: 0 publications found

Genes affected

EPM2AIP1 (HGNC:19735): (EPM2A interacting protein 1) The EPM2A gene, which encodes laforin, is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The protein encoded by this gene binds to laforin, but its function is not known. This gene is intronless. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
EPM2AIP1	NM_014805.4	c.1558T>C	p.Tyr520His	missense_variant	Exon 1 of 1	ENST00000322716.8	NP_055620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2AIP1	ENST00000322716.8	c.1558T>C	p.Tyr520His	missense_variant	Exon 1 of 1	6	NM_014805.4	ENSP00000406027.1
EPM2AIP1	ENST00000624586.1	c.387+361T>C		intron_variant	Intron 1 of 1	5		ENSP00000485091.1
EPM2AIP1	ENST00000623924.1	c.63-1085T>C		intron_variant	Intron 1 of 2	5		ENSP00000485489.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1558T>C (p.Y520H) alteration is located in exon 1 (coding exon 1) of the EPM2AIP1 gene. This alteration results from a T to C substitution at nucleotide position 1558, causing the tyrosine (Y) at amino acid position 520 to be replaced by a histidine (H). 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	Pathogenic	0.86
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0066	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.20
Sift	Benign	0.18	T
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.51
MutPred		0.73		Loss of helix (P = 0.0558);
MVP		0.29
MPC		1.7
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.22
gMVP		0.61
Mutation Taster		=92/8	polymorphism

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

hg19: chr3-37033011;