chr3-186783611-A-T

Variant names:

• chr3-186783611-A-T
• rs571299759
• NM_001967.4:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001967.4(EIF4A2):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: EIF4A2 NM_001967.4 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.34

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]

ENSG00000263826 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 18 codons. Genomic position: 186784454. Lost 0.042 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4A2	NM_001967.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 11	ENST00000323963.10	NP_001958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4A2	ENST00000323963.10	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 11	1	NM_001967.4	ENSP00000326381.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74392

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.0091	T;T;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.55	N;N;N;N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;D;T
Sift4G	Pathogenic	0.0	D;D;D;T
Polyphen		0.0060, 0.011	.;.;B;B
Vest4		0.91, 0.84
MutPred		0.99		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.56

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: rs571299759; hg19: chr3-186501400;