rs587777204

chr17-80138200-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_014740.4(EIF4A3):c.809A>G(p.Asp270Gly) 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). Synonymous variant affecting the same amino acid position (i.e. D270D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4A3 NM_014740.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.49

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a mutagenesis_site Loss of CWC22-binding and loss of incorporation into EJCs; when associated with K-273. (size 0) in uniprot entity IF4A3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EIF4A3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• PP5: Variant 17-80138200-T-C is Pathogenic according to our data. Variant chr17-80138200-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 101503.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4A3	NM_014740.4	c.809A>G	p.Asp270Gly	missense_variant	8/12	ENST00000649764.2
EIF4A3	NM_001411099.1	c.746A>G	p.Asp249Gly	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4A3	ENST00000649764.2	c.809A>G	p.Asp270Gly	missense_variant	8/12		NM_014740.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Richieri Costa-Pereira syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D;.;.;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.017	D;.;.;.
Polyphen		0.92	P;P;P;.
Vest4		0.92
MutPred		0.58		Loss of stability (P = 0.085);Loss of stability (P = 0.085);Loss of stability (P = 0.085);.;
MVP		0.85
MPC		1.6
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.87

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: rs587777204; hg19: chr17-78111999;