3-186783602-TTTCGGATCATGTCTGGTGGC-T

Variant names:

• chr3-186783602-TTTCGGATCATGTCTGGTGGC-T
• NM_001967.4:c.-7_13delTCGGATCATGTCTGGTGGCT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001967.4(EIF4A2):​c.-7_13delTCGGATCATGTCTGGTGGCT​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF4A2 NM_001967.4 frameshift, start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• 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

ENSG00000263826 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.

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.-7_13delTCGGATCATGTCTGGTGGCT	p.Met1fs	frameshift start_lost	Exon 1 of 11	NP_001958.2	Q14240-1
	EIF4A2	NM_001967.4	MANE Select	c.-7_13delTCGGATCATGTCTGGTGGCT		5_prime_UTR	Exon 1 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.-7_13delTCGGATCATGTCTGGTGGCT	p.Met1fs	frameshift start_lost	Exon 1 of 11	ENSP00000326381.5	Q14240-1
	EIF4A2	ENST00000440191.6	TSL:1	c.-7_13delTCGGATCATGTCTGGTGGCT	p.Met1fs	frameshift start_lost	Exon 1 of 11	ENSP00000398370.2	Q14240-2
	EIF4A2	ENST00000323963.10	TSL:1 MANE Select	c.-7_13delTCGGATCATGTCTGGTGGCT		5_prime_UTR	Exon 1 of 11	ENSP00000326381.5	Q14240-1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	EIF4A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr3-186501391;