chr14-67380676-A-G

Position:

• chr14-67380676-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004094.5(EIF2S1):​c.491A>G​(p.Asp164Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,413,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: EIF2S1 NM_004094.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754
• BS2: High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2S1	NM_004094.5	c.491A>G	p.Asp164Gly	missense_variant	5/8	ENST00000256383.11	NP_004085.1
GPHN	XM_047430879.1	c.1312+321890A>G		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2S1	ENST00000256383.11	c.491A>G	p.Asp164Gly	missense_variant	5/8	1	NM_004094.5	ENSP00000256383.4
EIF2S1	ENST00000466499.6	c.491A>G	p.Asp164Gly	missense_variant	4/7	1		ENSP00000425299.1
EIF2S1	ENST00000557310.5	c.491A>G	p.Asp164Gly	missense_variant	5/7	2		ENSP00000451975.1
EIF2S1	ENST00000555876.1	c.359A>G	p.Asp120Gly	missense_variant	4/6	2		ENSP00000452034.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000136 AC: 3 AN: 219928 Hom.: 0 AF XY: 0.00000832 AC XY: 1 AN XY: 120212

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: 0.0000405

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000290 AC: 41 AN: 1413934 Hom.: 0 Cov.: 28 AF XY: 0.0000313 AC XY: 22 AN XY: 703020

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000367

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.491A>G (p.D164G) alteration is located in exon 5 (coding exon 4) of the EIF2S1 gene. This alteration results from a A to G substitution at nucleotide position 491, causing the aspartic acid (D) at amino acid position 164 to be replaced by a glycine (G). 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	0.14
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;.
M_CAP	Benign	0.0091	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.011	B;.;B
Vest4		0.58
MutPred		0.53		Gain of catalytic residue at P160 (P = 0.0211);Gain of catalytic residue at P160 (P = 0.0211);Gain of catalytic residue at P160 (P = 0.0211);
MVP		0.88
MPC		1.5
ClinPred		0.79	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs765926237; hg19: chr14-67847393;