NM_014805.4:c.1615A>C

Variant names:

• chr3-36991463-T-G
• rs755852800
• NM_014805.4:c.1615A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014805.4(EPM2AIP1):​c.1615A>C​(p.Ile539Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. I539V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPM2AIP1 NM_014805.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.990
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16799635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2AIP1	NM_014805.4	c.1615A>C	p.Ile539Leu	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.1615A>C	p.Ile539Leu	missense_variant	Exon 1 of 1	6	NM_014805.4	ENSP00000406027.1
EPM2AIP1	ENST00000624586.1	c.387+418A>C		intron_variant	Intron 1 of 1	5		ENSP00000485091.1
EPM2AIP1	ENST00000623924.1	c.63-1028A>C		intron_variant	Intron 1 of 2	5		ENSP00000485489.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.99
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.032
Sift	Benign	0.34	T
Sift4G	Benign	0.45	T
Polyphen		0.026	B
Vest4		0.28
MutPred		0.71		Loss of methylation at K541 (P = 0.0582);
MVP		0.17
MPC		0.58
ClinPred		0.054	T
GERP RS		2.0
Varity_R		0.079
gMVP		0.46
Mutation Taster		=97/3	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

dbSNP: rs755852800; hg19: chr3-37032954;