chr22-36517411-T-C

Variant names:

• chr22-36517411-T-C
• NM_003753.4:c.880A>G

Variant summary

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

The NM_003753.4(EIF3D):​c.880A>G​(p.Thr294Ala) 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: 32)
• Consequence: EIF3D NM_003753.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33

Genes affected

EIF3D (HGNC:3278): (eukaryotic translation initiation factor 3 subunit D) Eukaryotic translation initiation factor-3 (eIF3), the largest of the eIFs, is a multiprotein complex composed of at least ten nonidentical subunits. The complex binds to the 40S ribosome and helps maintain the 40S and 60S ribosomal subunits in a dissociated state. It is also thought to play a role in the formation of the 40S initiation complex by interacting with the ternary complex of eIF2/GTP/methionyl-tRNA, and by promoting mRNA binding. The protein encoded by this gene is the major RNA binding subunit of the eIF3 complex. [provided by RefSeq, Jul 2008]

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, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3D	NM_003753.4	c.880A>G	p.Thr294Ala	missense_variant	Exon 10 of 15	ENST00000216190.13	NP_003744.1
EIF3D	XM_047441560.1	c.*12A>G		3_prime_UTR_variant	Exon 10 of 10		XP_047297516.1
EIF3D	NR_156418.2	n.1043A>G		non_coding_transcript_exon_variant	Exon 10 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF3D	ENST00000216190.13	c.880A>G	p.Thr294Ala	missense_variant	Exon 10 of 15	1	NM_003753.4	ENSP00000216190.8
EIF3D	ENST00000405442.5	c.880A>G	p.Thr294Ala	missense_variant	Exon 10 of 15	5		ENSP00000385812.1
EIF3D	ENST00000458572.1	n.*12A>G		non_coding_transcript_exon_variant	Exon 3 of 7	3		ENSP00000391061.2
EIF3D	ENST00000458572.1	n.*12A>G		3_prime_UTR_variant	Exon 3 of 7	3		ENSP00000391061.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.880A>G (p.T294A) alteration is located in exon 10 (coding exon 9) of the EIF3D gene. This alteration results from a A to G substitution at nucleotide position 880, causing the threonine (T) at amino acid position 294 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.4	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.60		Loss of phosphorylation at T294 (P = 0.0422);Loss of phosphorylation at T294 (P = 0.0422);
MVP		0.63
MPC		2.1
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.79
gMVP		0.78

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: chr22-36913458;