chr17-80144218-G-T

Position:

• chr17-80144218-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014740.4(EIF4A3):​c.196C>A​(p.Gln66Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF4A3 NM_014740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4A3	NM_014740.4	c.196C>A	p.Gln66Lys	missense_variant	2/12	ENST00000649764.2	NP_055555.1
EIF4A3	NM_001411099.1	c.196C>A	p.Gln66Lys	missense_variant	2/11		NP_001398028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4A3	ENST00000649764.2	c.196C>A	p.Gln66Lys	missense_variant	2/12		NM_014740.4	ENSP00000497641.1
EIF4A3	ENST00000647795.1	c.196C>A	p.Gln66Lys	missense_variant	3/13			ENSP00000497661.1
EIF4A3	ENST00000576547.2	c.196C>A	p.Gln66Lys	missense_variant	2/11	3		ENSP00000460439.2
EIF4A3	ENST00000575957.1	n.374C>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2024

The c.196C>A (p.Q66K) alteration is located in exon 2 (coding exon 2) of the EIF4A3 gene. This alteration results from a C to A substitution at nucleotide position 196, causing the glutamine (Q) at amino acid position 66 to be replaced by a lysine (K). 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	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.027	D;.;.;.
Sift4G	Benign	0.12	T;.;.;T
Polyphen		0.10	B;B;B;.
Vest4		0.64
MutPred		0.60		Gain of methylation at Q66 (P = 0.0039);Gain of methylation at Q66 (P = 0.0039);Gain of methylation at Q66 (P = 0.0039);Gain of methylation at Q66 (P = 0.0039);
MVP		0.80
MPC		2.5
ClinPred		0.92	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.88

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: chr17-78118017;