3-184315822-GC-GCCCC

Variant names:

• chr3-184315822-G-GCCC
• rs1406170008
• NM_198241.3:c.30_32dupCCC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_198241.3(EIF4G1):​c.30_32dupCCC​(p.Pro11dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 1,392,450 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: not found (cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: EIF4G1 NM_198241.3 disruptive_inframe_insertion
• 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 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_198241.3. Strenght limited to Supporting due to length of the change: 1aa.

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.30_32dupCCC	p.Pro11dup	disruptive_inframe_insertion	Exon 3 of 33	NP_937884.2	Q04637-1
	EIF4G1	NM_001194946.2		c.30_32dupCCC	p.Pro11dup	disruptive_inframe_insertion	Exon 3 of 34	NP_001181875.2	Q04637-9
	EIF4G1	NM_001194947.2		c.30_32dupCCC	p.Pro11dup	disruptive_inframe_insertion	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.30_32dupCCC	p.Pro11dup	disruptive_inframe_insertion	Exon 3 of 33	ENSP00000316879.5	Q04637-1
	EIF4G1	ENST00000352767.7	TSL:1	c.30_32dupCCC	p.Pro11dup	disruptive_inframe_insertion	Exon 2 of 33	ENSP00000338020.4	Q04637-9
	EIF4G1	ENST00000382330.7	TSL:1	c.30_32dupCCC	p.Pro11dup	disruptive_inframe_insertion	Exon 3 of 34	ENSP00000371767.3	Q04637-9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000345 AC: 48 AN: 1392450 Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 19 AN XY: 687148

⚠️ 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: 31494

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: 0.0000126 AC: 1 AN: 79130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.0000429 AC: 46 AN: 1072818

Other (OTH) AF: 0.0000173 AC: 1 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

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;