NM_001967.4:c.256A>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 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
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

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.256A>C	p.Thr86Pro	missense	Exon 4 of 11	NP_001958.2	Q14240-1
	SNORD2	NR_002587.1		n.*144A>C		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4A2	ENST00000323963.10	TSL:1 MANE Select	c.256A>C	p.Thr86Pro	missense	Exon 4 of 11	ENSP00000326381.5	Q14240-1
	EIF4A2	ENST00000440191.6	TSL:1	c.259A>C	p.Thr87Pro	missense	Exon 4 of 11	ENSP00000398370.2	Q14240-2
	EIF4A2	ENST00000426808.5	TSL:1	n.208+313A>C		intron	N/A	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	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.79		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
Mutation Taster		=19/81	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: chr3-186502798;