3-184249753-A-G

Position:

• chr3-184249753-A-G

Variant summary

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

The NM_032331.4(EEF1AKMT4):​c.59A>G​(p.Tyr20Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EEF1AKMT4 NM_032331.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

Genes affected

EEF1AKMT4 (HGNC:53611): (EEF1A lysine methyltransferase 4) This gene encodes a member of the lysine-specific methyltransferase (KMT) family. The encoded enzyme catalyzes the methylation of lysine-36 of the eukaryotic translation elongation factor 1 alpha. Methylation by this enzyme may affect endoplasmic reticulum-related processes. [provided by RefSeq, Jul 2017]

EEF1AKMT4-ECE2 (HGNC:53615): (EEF1AKMT4-ECE2 readthrough) This gene represents naturally occurring readthrough transcription between adjacent genes eukaryotic translation elongation factor 1 alpha lysine methyltransferase 4 (GeneID: 110599564) and endothelin converting enzyme 2 (GeneID:9718). The readthrough transcript representing this gene encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jul 2017]

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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EEF1AKMT4	NM_032331.4	c.59A>G	p.Tyr20Cys	missense_variant	1/3	ENST00000324557.9	NP_115707.2
EEF1AKMT4-ECE2	NM_014693.4	c.59A>G	p.Tyr20Cys	missense_variant	1/19		NP_055508.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEF1AKMT4	ENST00000324557.9	c.59A>G	p.Tyr20Cys	missense_variant	1/3	1	NM_032331.4	ENSP00000314295.5
EEF1AKMT4-ECE2	ENST00000402825.7	c.59A>G	p.Tyr20Cys	missense_variant	1/19	1		ENSP00000384223.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Aug 15, 2023

The c.59A>G (p.Y20C) alteration is located in exon 1 (coding exon 1) of the ECE2 gene. This alteration results from a A to G substitution at nucleotide position 59, causing the tyrosine (Y) at amino acid position 20 to be replaced by a cysteine (C). 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	0.63
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.75	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.1	D;N
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.80
MutPred		0.51		Gain of glycosylation at Y25 (P = 0.0054);Gain of glycosylation at Y25 (P = 0.0054);
MVP		0.93
MPC		0.85
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-183967541;