chr3-170893408-C-G

Position:

• chr3-170893408-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020390.6(EIF5A2):​c.414G>C​(p.Met138Ile) 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. 14/21 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: EIF5A2 NM_020390.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

EIF5A2 (HGNC:3301): (eukaryotic translation initiation factor 5A2) Predicted to enable translation elongation factor activity. Predicted to be involved in positive regulation of translational elongation. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15048137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF5A2	NM_020390.6	c.414G>C	p.Met138Ile	missense_variant	5/5	ENST00000295822.7	NP_065123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF5A2	ENST00000295822.7	c.414G>C	p.Met138Ile	missense_variant	5/5	1	NM_020390.6	ENSP00000295822	P1
EIF5A2	ENST00000487522.5	c.282G>C	p.Met94Ile	missense_variant	4/4	3		ENSP00000418305
EIF5A2	ENST00000474096.5	c.*56G>C		3_prime_UTR_variant	5/5	4		ENSP00000418370
EIF5A2	ENST00000460117.5	n.246G>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The c.414G>C (p.M138I) alteration is located in exon 5 (coding exon 4) of the EIF5A2 gene. This alteration results from a G to C substitution at nucleotide position 414, causing the methionine (M) at amino acid position 138 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.49	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.66	N;N
REVEL	Benign	0.046
Sift	Benign	0.32	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.46		Loss of loop (P = 0.0112);.;
MVP		0.55
MPC		0.65
ClinPred		0.30	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.27

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: rs754601182; hg19: chr3-170611197;