chr3-184328682-C-G

Variant names:

• chr3-184328682-C-G
• rs2230571
• NM_198241.3:c.4005C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198241.3(EIF4G1):​c.4005C>G​(p.His1335Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H1335H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4G1 NM_198241.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 28 publications found

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]

EIF4G1 Gene-Disease associations (from GenCC):

• Parkinson disease 18, autosomal dominant, susceptibility to

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G1	NM_198241.3	c.4005C>G	p.His1335Gln	missense_variant	Exon 27 of 33	ENST00000346169.7	NP_937884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4G1	ENST00000346169.7	c.4005C>G	p.His1335Gln	missense_variant	Exon 27 of 33	1	NM_198241.3	ENSP00000316879.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 15235

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.50	D
LIST_S2	Pathogenic	0.97	D;D;D;D;.;D;D;D;.;D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		-1.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.4	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.77
MutPred		0.51		Gain of catalytic residue at H1335 (P = 0.0706);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.73
MPC		1.2
ClinPred		0.99	D
GERP RS		-4.2
Varity_R		0.82
gMVP		0.66
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

dbSNP: rs2230571; hg19: chr3-184046470;