6-8102509-C-T

Variant names:

• chr6-8102509-C-T
• rs575826954
• NM_004280.5:c.13G>A

Variant summary

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

The NM_004280.5(EEF1E1):​c.13G>A​(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000075 (0 hom.)
• Consequence: EEF1E1 NM_004280.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

Genes affected

EEF1E1 (HGNC:3212): (eukaryotic translation elongation factor 1 epsilon 1) This gene encodes a multifunctional protein that localizes to both the cytoplasm and nucleus. In the cytoplasm, the encoded protein is an auxiliary component of the macromolecular aminoacyl-tRNA synthase complex. However, its mouse homolog has been shown to translocate to the nucleus in response to DNA damage, and it plays a positive role in ATM/ATR-mediated p53 activation. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream MUTED (muted homolog) gene. An EEF1E1-related pseudogene has been identified on chromosome 2. [provided by RefSeq, Dec 2010]

EEF1E1-BLOC1S5 (HGNC:49187): (EEF1E1-BLOC1S5 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) and MUTED (muted homolog) genes on chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

ENSG00000232234 (HGNC:):

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=0.17090723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EEF1E1	NM_004280.5	c.13G>A	p.Ala5Thr	missense_variant	Exon 1 of 4	ENST00000379715.10	NP_004271.1
EEF1E1	NM_001135650.2	c.13G>A	p.Ala5Thr	missense_variant	Exon 1 of 4		NP_001129122.1
EEF1E1-BLOC1S5	NR_037618.1	n.87G>A		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EEF1E1	ENST00000379715.10	c.13G>A	p.Ala5Thr	missense_variant	Exon 1 of 4	1	NM_004280.5	ENSP00000369038.5
EEF1E1-BLOC1S5	ENST00000397456.2	n.13G>A		non_coding_transcript_exon_variant	Exon 1 of 7	3		ENSP00000380597.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248332 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458506 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000199

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13G>A (p.A5T) alteration is located in exon 1 (coding exon 1) of the EEF1E1 gene. This alteration results from a G to A substitution at nucleotide position 13, causing the alanine (A) at amino acid position 5 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;.
Eigen	Benign	-0.064
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.055
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0070	.;B;.
Vest4		0.30
MutPred		0.35		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.30
MPC		0.27
ClinPred		0.83	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
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: rs575826954; hg19: chr6-8102742;