17-7311587-C-A

Position:

• chr17-7311587-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001970.5(EIF5A):​c.412C>A​(p.Leu138Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: EIF5A NM_001970.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.978

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Eukaryotic translation initiation factor 5A-1 (size 152) in uniprot entity IF5A1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_001970.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EIF5A. . Gene score misZ 2.407 (greater than the threshold 3.09). Trascript score misZ 4.4819 (greater than threshold 3.09). GenCC has associacion of gene with Faundes-Banka syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35586345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF5A	NM_001970.5	c.412C>A	p.Leu138Met	missense_variant	5/6	ENST00000336458.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF5A	ENST00000336458.13	c.412C>A	p.Leu138Met	missense_variant	5/6	1	NM_001970.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.0065
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;.;.;T;.;.;.;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N;N;.;.;.;N;.;.;N
REVEL	Benign	0.062
Sift	Benign	0.27	T;T;.;.;.;T;.;.;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T
Polyphen		0.36	B;B;B;.;B;B;B;.;B
Vest4		0.43
MutPred		0.58		.;Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.64
MPC		2.0
ClinPred		0.85	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.78

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: rs2072829786; hg19: chr17-7214906;