NM_001967.4:c.365T>G

Variant names:

• chr3-186785899-T-G
• NM_001967.4:c.365T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001967.4(EIF4A2):​c.365T>G​(p.Leu122Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF4A2 NM_001967.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

Genes affected

EIF4A2 (HGNC:3284): (eukaryotic translation initiation factor 4A2) Enables ATP hydrolysis activity. Involved in negative regulation of RNA-directed 5'-3' RNA polymerase activity. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

EIF4A2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and speech delay, with or without seizures

  Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.895 (above the threshold of 3.09). Trascript score misZ: 5.45 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with hypotonia and speech delay, with or without seizures.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38235596).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001967.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4A2	NM_001967.4	MANE Select	c.365T>G	p.Leu122Arg	missense	Exon 5 of 11	NP_001958.2	Q14240-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4A2	ENST00000323963.10	TSL:1 MANE Select	c.365T>G	p.Leu122Arg	missense	Exon 5 of 11	ENSP00000326381.5	Q14240-1
	EIF4A2	ENST00000440191.6	TSL:1	c.368T>G	p.Leu123Arg	missense	Exon 5 of 11	ENSP00000398370.2	Q14240-2
	EIF4A2	ENST00000426808.5	TSL:1	n.225T>G		non_coding_transcript_exon	Exon 4 of 10	ENSP00000392686.1	E9PBH4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.056
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.13	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Benign	0.50	T
Sift4G	Benign	0.66	T
Polyphen		0.0060	B
Vest4		0.72
MutPred		0.39		Gain of MoRF binding (P = 0.0067)
MVP		0.83
MPC		2.1
ClinPred		0.84	D
GERP RS		3.6
Varity_R		0.64
gMVP		0.93
Mutation Taster		=46/54	disease causing

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

Other links and lift over

hg19: chr3-186503688;