3-186785646-G-A

Variant names:

• chr3-186785646-G-A
• rs1426810
• NM_001967.4:c.349-237G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001967.4(EIF4A2):​c.349-237G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 474,074 control chromosomes in the GnomAD database, including 107,230 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (37171 hom., cov: 33)
  • Exomes 𝑓: 0.66 (70059 hom.)
• Consequence: EIF4A2 NM_001967.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 15 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: Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4A2	NM_001967.4	MANE Select	c.349-237G>A		intron	N/A	NP_001958.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4A2	ENST00000323963.10	TSL:1 MANE Select	c.349-237G>A		intron	N/A	ENSP00000326381.5
	EIF4A2	ENST00000440191.6	TSL:1	c.352-237G>A		intron	N/A	ENSP00000398370.2
	EIF4A2	ENST00000426808.5	TSL:1	n.209-237G>A		intron	N/A	ENSP00000392686.1

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105503 AN: 151992 Hom.: 37118 Cov.: 33

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.605

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.672

GnomAD4 exome AF: 0.655 AC: 210935 AN: 321964 Hom.: 70059 Cov.: 4 AF XY: 0.652 AC XY: 108203 AN XY: 165982

African (AFR) AF: 0.803 AC: 8862 AN: 11040

American (AMR) AF: 0.722 AC: 9780 AN: 13552

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 6408 AN: 10510

East Asian (EAS) AF: 0.802 AC: 21546 AN: 26850

South Asian (SAS) AF: 0.602 AC: 12138 AN: 20166

European-Finnish (FIN) AF: 0.725 AC: 14932 AN: 20590

Middle Eastern (MID) AF: 0.658 AC: 972 AN: 1478

European-Non Finnish (NFE) AF: 0.623 AC: 123542 AN: 198370

Other (OTH) AF: 0.657 AC: 12755 AN: 19408

GnomAD4 genome AF: 0.694 AC: 105614 AN: 152110 Hom.: 37171 Cov.: 33 AF XY: 0.697 AC XY: 51838 AN XY: 74328

African (AFR) AF: 0.798 AC: 33121 AN: 41496

American (AMR) AF: 0.726 AC: 11096 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2144 AN: 3470

East Asian (EAS) AF: 0.749 AC: 3875 AN: 5174

South Asian (SAS) AF: 0.626 AC: 3020 AN: 4822

European-Finnish (FIN) AF: 0.730 AC: 7718 AN: 10566

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.625 AC: 42463 AN: 67984

Other (OTH) AF: 0.671 AC: 1419 AN: 2114

Alfa AF: 0.637 Hom.: 58881

Bravo AF: 0.696

Asia WGS AF: 0.732 AC: 2544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.76
DANN	Benign	0.58
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs1426810; hg19: chr3-186503435;