14-67380501-T-G

Variant names:

• chr14-67380501-T-G
• rs8008724
• NM_004094.5:c.474-158T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004094.5(EIF2S1):​c.474-158T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,184 control chromosomes in the GnomAD database, including 3,200 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (3200 hom., cov: 32)
• Consequence: EIF2S1 NM_004094.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.156
• Publications: 5 publications found

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]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2S1	NM_004094.5	c.474-158T>G		intron_variant	Intron 4 of 7	ENST00000256383.11	NP_004085.1
GPHN	XM_047430879.1	c.1312+321715T>G		intron_variant	Intron 14 of 14		XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2S1	ENST00000256383.11	c.474-158T>G		intron_variant	Intron 4 of 7	1	NM_004094.5	ENSP00000256383.4
EIF2S1	ENST00000466499.6	c.474-158T>G		intron_variant	Intron 3 of 6	1		ENSP00000425299.1
EIF2S1	ENST00000557310.5	c.474-158T>G		intron_variant	Intron 4 of 6	2		ENSP00000451975.1
EIF2S1	ENST00000555876.1	c.342-158T>G		intron_variant	Intron 3 of 5	2		ENSP00000452034.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22706 AN: 152066 Hom.: 3192 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.150

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22747 AN: 152184 Hom.: 3200 Cov.: 32 AF XY: 0.156 AC XY: 11580 AN XY: 74424

African (AFR) AF: 0.315 AC: 13048 AN: 41482

American (AMR) AF: 0.215 AC: 3294 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 232 AN: 3472

East Asian (EAS) AF: 0.421 AC: 2180 AN: 5172

South Asian (SAS) AF: 0.260 AC: 1256 AN: 4826

European-Finnish (FIN) AF: 0.0538 AC: 571 AN: 10604

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.0267 AC: 1819 AN: 68014

Other (OTH) AF: 0.149 AC: 316 AN: 2114

Alfa AF: 0.106 Hom.: 739

Bravo AF: 0.170

Asia WGS AF: 0.295 AC: 1028 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.1
DANN	Benign	0.86
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs8008724; hg19: chr14-67847218;