3-184316166-T-C

Variant names:

• chr3-184316166-T-C
• rs1391313939
• NM_198241.3:c.95T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198241.3(EIF4G1):​c.95T>C​(p.Val32Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EIF4G1 NM_198241.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.41

Genes affected

EIF4G1 (HGNC:3296): (eukaryotic translation initiation factor 4 gamma 1) The protein encoded by this gene is a component of the multi-subunit protein complex EIF4F. This complex facilitates the recruitment of mRNA to the ribosome, which is a rate-limiting step during the initiation phase of protein synthesis. The recognition of the mRNA cap and the ATP-dependent unwinding of 5'-terminal secondary structure is catalyzed by factors in this complex. The subunit encoded by this gene is a large scaffolding protein that contains binding sites for other members of the EIF4F complex. A domain at its N-terminus can also interact with the poly(A)-binding protein, which may mediate the circularization of mRNA during translation. Alternative splicing results in multiple transcript variants, some of which are derived from alternative promoter usage. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2378195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G1	NM_198241.3	c.95T>C	p.Val32Ala	missense_variant	Exon 4 of 33	ENST00000346169.7	NP_937884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4G1	ENST00000346169.7	c.95T>C	p.Val32Ala	missense_variant	Exon 4 of 33	1	NM_198241.3	ENSP00000316879.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251074 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95T>C (p.V32A) alteration is located in exon 4 (coding exon 2) of the EIF4G1 gene. This alteration results from a T to C substitution at nucleotide position 95, causing the valine (V) at amino acid position 32 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	0.57
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;T;.;T;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;T;D;D;.;D;D;T;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;.;M;.;.;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N;N;N;N;N;N;D;N;N
REVEL	Benign	0.058
Sift	Uncertain	0.010	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;.;.;.;.;.;.;.;.
Vest4		0.69
MutPred		0.21		Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);Loss of glycosylation at S34 (P = 0.0147);
MVP		0.32
MPC		1.8
ClinPred		0.90	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.36

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: rs1391313939; hg19: chr3-184033954;