3-186785009-A-C

Variant names:

• chr3-186785009-A-C
• NM_001967.4:c.256A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001967.4(EIF4A2):​c.256A>C​(p.Thr86Pro) 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 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: 8.74

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]

SNORD2 (HGNC:32678): (small nucleolar RNA, C/D box 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4A2	NM_001967.4	c.256A>C	p.Thr86Pro	missense_variant	Exon 4 of 11	ENST00000323963.10	NP_001958.2
SNORD2	NR_002587.1	n.*144A>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4A2	ENST00000323963.10	c.256A>C	p.Thr86Pro	missense_variant	Exon 4 of 11	1	NM_001967.4	ENSP00000326381.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 17, 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	.;M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D;D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.77, 0.78
MutPred		0.79		Gain of ubiquitination at K83 (P = 0.0797);Gain of ubiquitination at K83 (P = 0.0797);.;.;
MVP		0.87
MPC		3.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-186502798;