3-184315822-GC-GCCCCCCCCCCC

Variant names:

• chr3-184315822-G-GCCCCCCCCCC
• rs1406170008
• NM_198241.3:c.32_33insCCCCCCCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_198241.3(EIF4G1):​c.32_33insCCCCCCCCCC​(p.Ala13ProfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,392,436 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EIF4G1 NM_198241.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 0 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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.993 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198241.3. 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
	EIF4G1	NM_198241.3	MANE Select	c.32_33insCCCCCCCCCC	p.Ala13ProfsTer45	frameshift	Exon 3 of 33	NP_937884.2	Q04637-1
	EIF4G1	NM_001194946.2		c.32_33insCCCCCCCCCC	p.Ala13ProfsTer52	frameshift	Exon 3 of 34	NP_001181875.2	Q04637-9
	EIF4G1	NM_001194947.2		c.32_33insCCCCCCCCCC	p.Ala13ProfsTer52	frameshift	Exon 2 of 33	NP_001181876.2	Q04637-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4G1	ENST00000346169.7	TSL:1 MANE Select	c.32_33insCCCCCCCCCC	p.Ala13ProfsTer45	frameshift	Exon 3 of 33	ENSP00000316879.5	Q04637-1
	EIF4G1	ENST00000352767.7	TSL:1	c.32_33insCCCCCCCCCC	p.Ala13ProfsTer52	frameshift	Exon 2 of 33	ENSP00000338020.4	Q04637-9
	EIF4G1	ENST00000382330.7	TSL:1	c.32_33insCCCCCCCCCC	p.Ala13ProfsTer52	frameshift	Exon 3 of 34	ENSP00000371767.3	Q04637-9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 62 AN: 1392436 Hom.: 0 Cov.: 31 AF XY: 0.0000407 AC XY: 28 AN XY: 687138

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31496

American (AMR) AF: 0.00 AC: 0 AN: 35732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 35746

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.0000522 AC: 56 AN: 1072806

Other (OTH) AF: 0.0000693 AC: 4 AN: 57738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74190

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1406170008; hg19: chr3-184033610;