chr17-80146888-T-C

Position:

• chr17-80146888-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014740.4(EIF4A3):​c.74A>G​(p.Lys25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: EIF4A3 NM_014740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20174858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4A3	NM_014740.4	c.74A>G	p.Lys25Arg	missense_variant	1/12	ENST00000649764.2	NP_055555.1
EIF4A3	NM_001411099.1	c.74A>G	p.Lys25Arg	missense_variant	1/11		NP_001398028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4A3	ENST00000649764.2	c.74A>G	p.Lys25Arg	missense_variant	1/12		NM_014740.4	ENSP00000497641.1
EIF4A3	ENST00000647795.1	c.74A>G	p.Lys25Arg	missense_variant	2/13			ENSP00000497661.1
EIF4A3	ENST00000576547.2	c.74A>G	p.Lys25Arg	missense_variant	1/11	3		ENSP00000460439.2
EIF4A3	ENST00000575957.1	n.252A>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246898 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459142 Hom.: 0 Cov.: 32 AF XY: 0.00000689 AC XY: 5 AN XY: 725990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

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

Sep 29, 2023

The c.74A>G (p.K25R) alteration is located in exon 1 (coding exon 1) of the EIF4A3 gene. This alteration results from a A to G substitution at nucleotide position 74, causing the lysine (K) at amino acid position 25 to be replaced by an arginine (R). 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	0.083
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Benign	-0.086
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;.;D;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.57	N;.;.;.
REVEL	Benign	0.069
Sift	Benign	0.30	T;.;.;.
Sift4G	Benign	0.24	T;.;.;T
Polyphen		0.0	B;B;B;.
Vest4		0.41
MutPred		0.28		Loss of ubiquitination at K25 (P = 0.0027);Loss of ubiquitination at K25 (P = 0.0027);Loss of ubiquitination at K25 (P = 0.0027);Loss of ubiquitination at K25 (P = 0.0027);
MVP		0.28
MPC		1.0
ClinPred		0.40	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.40
gMVP		0.53

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: rs1167145572; hg19: chr17-78120687;