chr17-7309778-C-A

Position:

• chr17-7309778-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM1 PM2 PP2 PP3 PP5

The NM_001970.5(EIF5A):​c.143C>A​(p.Thr48Asn) 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF5A NM_001970.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.39

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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 region_of_interest Interaction with DOHH (size 70) in uniprot entity IF5A1_HUMAN there are 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant 17-7309778-C-A is Pathogenic according to our data. Variant chr17-7309778-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1164078.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-7309778-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF5A	NM_001970.5	c.143C>A	p.Thr48Asn	missense_variant	2/6	ENST00000336458.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF5A	ENST00000336458.13	c.143C>A	p.Thr48Asn	missense_variant	2/6	1	NM_001970.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Faundes-Banka syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;D;D;.;D;D;D;T;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;.;.;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Pathogenic	3.5	.;M;M;.;M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-4.7	D;D;.;.;.;D;.;.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D;.;.;.;D;.;.;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;P;P;.;P;P;P;.;P
Vest4		0.68
MutPred		0.52		.;Loss of phosphorylation at T48 (P = 0.0433);Loss of phosphorylation at T48 (P = 0.0433);Loss of phosphorylation at T48 (P = 0.0433);Loss of phosphorylation at T48 (P = 0.0433);Loss of phosphorylation at T48 (P = 0.0433);Loss of phosphorylation at T48 (P = 0.0433);Loss of phosphorylation at T48 (P = 0.0433);Loss of phosphorylation at T48 (P = 0.0433);
MVP		0.73
MPC		3.0
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.93

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: chr17-7213097;