chr17-7311422-C-T

Position:

• chr17-7311422-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001970.5(EIF5A):​c.343C>T​(p.Pro115Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P115A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF5A NM_001970.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.26

Genes affected

EIF5A (HGNC:3300): (eukaryotic translation initiation factor 5A) Enables U6 snRNA binding activity and protein N-terminus binding activity. Involved in several processes, including cellular response to virus; positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator; and tumor necrosis factor-mediated signaling pathway. Located in annulate lamellae; cytoplasm; and nucleus. Part of nuclear pore. [provided by Alliance of Genome Resources, Apr 2022]

GPS2 (HGNC:4550): (G protein pathway suppressor 2) This gene encodes a protein involved in G protein-mitogen-activated protein kinase (MAPK) signaling cascades. When overexpressed in mammalian cells, this gene could potently suppress a RAS- and MAPK-mediated signal and interfere with JNK activity, suggesting that the function of this gene may be signal repression. The encoded protein is an integral subunit of the NCOR1-HDAC3 (nuclear receptor corepressor 1-histone deacetylase 3) complex, and it was shown that the complex inhibits JNK activation through this subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (activator protein 1) function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_001970.5 (EIF5A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Eukaryotic translation initiation factor 5A-1 (size 152) in uniprot entity IF5A1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_001970.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7311422-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 17-7311422-C-T is Pathogenic according to our data. Variant chr17-7311422-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1327680.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF5A	NM_001970.5	c.343C>T	p.Pro115Ser	missense_variant	4/6	ENST00000336458.13	NP_001961.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF5A	ENST00000336458.13	c.343C>T	p.Pro115Ser	missense_variant	4/6	1	NM_001970.5	ENSP00000336776.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2023

De novo variant with confirmed parentage in a patient with EIF5A-related neurodevelopmental disorder (Faundes et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33547280) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	.;D;D;.;D;D;D;T;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;.;D;.;.;.;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.4	.;M;M;.;M;M;M;.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.4	D;D;.;.;.;D;.;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.019	D;D;.;.;.;D;.;.;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D;D;D
Polyphen		0.94	P;P;P;.;P;P;P;.;P
Vest4		0.69
MutPred		0.76		.;Gain of phosphorylation at P115 (P = 0.0092);Gain of phosphorylation at P115 (P = 0.0092);Gain of phosphorylation at P115 (P = 0.0092);Gain of phosphorylation at P115 (P = 0.0092);Gain of phosphorylation at P115 (P = 0.0092);Gain of phosphorylation at P115 (P = 0.0092);Gain of phosphorylation at P115 (P = 0.0092);Gain of phosphorylation at P115 (P = 0.0092);
MVP		0.68
MPC		2.6
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.95

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: chr17-7214741;