3-184319800-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_198241.3(EIF4G1):c.536C>T(p.Thr179Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,438,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: EIF4G1 NM_198241.3 missense, splice_region
• Scores: Splicing: ADA: 0.9808
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EIF4G1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3616122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4G1	NM_198241.3	c.536C>T	p.Thr179Met	missense_variant, splice_region_variant	7/33	ENST00000346169.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4G1	ENST00000346169.7	c.536C>T	p.Thr179Met	missense_variant, splice_region_variant	7/33	1	NM_198241.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1438358 Hom.: 0 Cov.: 30 AF XY: 0.00000700 AC XY: 5 AN XY: 714368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000456

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease 18, autosomal dominant, susceptibility to Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Jan 07, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;.;.;T;.;T;.;.;T;.;.;T;.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;.;D;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.55
MutPred		0.29		Gain of glycosylation at T179 (P = 0.0146);.;.;.;Gain of glycosylation at T179 (P = 0.0146);.;.;.;.;.;.;Gain of glycosylation at T179 (P = 0.0146);.;.;.;.;.;
MVP		0.37
MPC		1.3
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Varity_R		0.41
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.59
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: rs981309467; hg19: chr3-184037588; COSMIC: COSV59994460; COSMIC: COSV59994460;