NM_004094.5:c.794A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004094.5(EIF2S1):​c.794A>G​(p.Lys265Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

EIF2S1
NM_004094.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29
Variant links:
Genes affected
EIF2S1 (HGNC:3265): (eukaryotic translation initiation factor 2 subunit alpha) The translation initiation factor EIF2 catalyzes the first regulated step of protein synthesis initiation, promoting the binding of the initiator tRNA to 40S ribosomal subunits. Binding occurs as a ternary complex of methionyl-tRNA, EIF2, and GTP. EIF2 is composed of 3 nonidentical subunits, the 36-kD EIF2-alpha subunit (EIF2S1), the 38-kD EIF2-beta subunit (EIF2S2; MIM 603908), and the 52-kD EIF2-gamma subunit (EIF2S3; MIM 300161). The rate of formation of the ternary complex is modulated by the phosphorylation state of EIF2-alpha (Ernst et al., 1987 [PubMed 2948954]).[supplied by OMIM, Feb 2010]
GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40451378).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EIF2S1NM_004094.5 linkc.794A>G p.Lys265Arg missense_variant Exon 7 of 8 ENST00000256383.11 NP_004085.1 P05198Q53XC0
GPHNXM_047430879.1 linkc.1312+323776A>G intron_variant Intron 14 of 14 XP_047286835.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EIF2S1ENST00000256383.11 linkc.794A>G p.Lys265Arg missense_variant Exon 7 of 8 1 NM_004094.5 ENSP00000256383.4 P05198

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 11, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.794A>G (p.K265R) alteration is located in exon 7 (coding exon 6) of the EIF2S1 gene. This alteration results from a A to G substitution at nucleotide position 794, causing the lysine (K) at amino acid position 265 to be replaced by an arginine (R). 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
0.086
BayesDel_addAF
Benign
-0.017
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.;T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D;.
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.40
T;T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
1.4
L;.;L
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.78
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.63
T;T;T
Sift4G
Benign
0.53
T;T;T
Polyphen
0.0010
B;.;B
Vest4
0.46
MutPred
0.35
Loss of ubiquitination at K265 (P = 0.0087);Loss of ubiquitination at K265 (P = 0.0087);Loss of ubiquitination at K265 (P = 0.0087);
MVP
0.57
MPC
0.85
ClinPred
0.80
D
GERP RS
5.7
Varity_R
0.27
gMVP
0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-67849279; API