NM_001970.5:c.316G>A

Variant names:

• chr17-7311395-G-A
• rs2072823177
• NM_001970.5:c.316G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_001970.5(EIF5A):​c.316G>A​(p.Gly106Arg) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF5A NM_001970.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.39
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.407 (below the threshold of 3.09). Trascript score misZ: 4.4819 (above the threshold of 3.09). GenCC associations: The gene is linked to Faundes-Banka syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 17-7311395-G-A is Pathogenic according to our data. Variant chr17-7311395-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3369240.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001970.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF5A	NM_001970.5	MANE Select	c.316G>A	p.Gly106Arg	missense	Exon 4 of 6	NP_001961.1	P63241-1
	EIF5A	NM_001143760.1		c.406G>A	p.Gly136Arg	missense	Exon 4 of 6	NP_001137232.1	P63241-2
	EIF5A	NM_001143761.1		c.316G>A	p.Gly106Arg	missense	Exon 4 of 6	NP_001137233.1	P63241-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF5A	ENST00000336458.13	TSL:1 MANE Select	c.316G>A	p.Gly106Arg	missense	Exon 4 of 6	ENSP00000336776.8	P63241-1
	EIF5A	ENST00000336452.11	TSL:1	c.406G>A	p.Gly136Arg	missense	Exon 4 of 6	ENSP00000336702.7	P63241-2
	EIF5A	ENST00000416016.2	TSL:1	c.316G>A	p.Gly106Arg	missense	Exon 4 of 6	ENSP00000396073.2	P63241-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
-	-	-	Faundes-Banka syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.016	D
Sift4G	Benign	0.094	T
Polyphen		0.78	P
Vest4		0.61
MutPred		0.70		Gain of solvent accessibility (P = 0.0014)
MVP		0.88
MPC		2.1
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2072823177; hg19: chr17-7214714; COSMIC: COSV59751035; COSMIC: COSV59751035;