17-80136093-G-T

Position:

• chr17-80136093-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_014740.4(EIF4A3):​c.1130C>A​(p.Ala377Asp) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4A3 NM_014740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

Genes affected

EIF4A3 (HGNC:18683): (eukaryotic translation initiation factor 4A3) This gene encodes a member of the DEAD box protein family. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a nuclear matrix protein. Its amino acid sequence is highly similar to the amino acid sequences of the translation initiation factors eIF4AI and eIF4AII, two other members of the DEAD box protein family. [provided by RefSeq, Jul 2008]

EIF4A3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EIF4A3. . Trascript score misZ 5.2164 (greater than threshold 3.09). GenCC has associacion of gene with Richieri Costa-Pereira syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4A3	NM_014740.4	c.1130C>A	p.Ala377Asp	missense_variant	11/12	ENST00000649764.2	NP_055555.1
EIF4A3	NM_001411099.1	c.1067C>A	p.Ala356Asp	missense_variant	10/11		NP_001398028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4A3	ENST00000649764.2	c.1130C>A	p.Ala377Asp	missense_variant	11/12		NM_014740.4	ENSP00000497641.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.5	M;M;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D;.;.;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;D;D;.
Vest4		0.92
MutPred		0.83		Loss of MoRF binding (P = 0.0645);Loss of MoRF binding (P = 0.0645);Loss of MoRF binding (P = 0.0645);.;
MVP		0.83
MPC		2.6
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.97
gMVP		1.0

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: chr17-78109892; COSMIC: COSV99484213; COSMIC: COSV99484213;