rs2293605

Variant names:

• chr3-184326645-C-T
• rs2293605
• NM_198241.3:c.3325+16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198241.3(EIF4G1):​c.3325+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,606,692 control chromosomes in the GnomAD database, including 10,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (810 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10176 hom.)
• Consequence: EIF4G1 NM_198241.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.672
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-184326645-C-T is Benign according to our data. Variant chr3-184326645-C-T is described in ClinVar as Benign. ClinVar VariationId is 518345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

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.3325+16C>T		intron	N/A	NP_937884.2	Q04637-1
	EIF4G1	NM_001194946.2		c.3346+16C>T		intron	N/A	NP_001181875.2	Q04637-9
	EIF4G1	NM_001194947.2		c.3346+16C>T		intron	N/A	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.3325+16C>T		intron	N/A	ENSP00000316879.5	Q04637-1
	EIF4G1	ENST00000352767.7	TSL:1	c.3346+16C>T		intron	N/A	ENSP00000338020.4	Q04637-9
	EIF4G1	ENST00000382330.7	TSL:1	c.3346+16C>T		intron	N/A	ENSP00000371767.3	Q04637-9

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13653 AN: 152170 Hom.: 811 Cov.: 33

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0876

GnomAD2 exomes AF: 0.106 AC: 26125 AN: 245644 AF XY: 0.109

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0293

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.115 AC: 167486 AN: 1454404 Hom.: 10176 Cov.: 32 AF XY: 0.116 AC XY: 83893 AN XY: 723818

African (AFR) AF: 0.0178 AC: 595 AN: 33476

American (AMR) AF: 0.108 AC: 4832 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2743 AN: 26130

East Asian (EAS) AF: 0.0179 AC: 710 AN: 39696

South Asian (SAS) AF: 0.105 AC: 9070 AN: 86176

European-Finnish (FIN) AF: 0.165 AC: 7662 AN: 46408

Middle Eastern (MID) AF: 0.0807 AC: 462 AN: 5722

European-Non Finnish (NFE) AF: 0.122 AC: 135293 AN: 1111754

Other (OTH) AF: 0.101 AC: 6119 AN: 60332

GnomAD4 genome AF: 0.0896 AC: 13648 AN: 152288 Hom.: 810 Cov.: 33 AF XY: 0.0908 AC XY: 6761 AN XY: 74460

African (AFR) AF: 0.0214 AC: 891 AN: 41578

American (AMR) AF: 0.0893 AC: 1366 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 341 AN: 3470

East Asian (EAS) AF: 0.0266 AC: 138 AN: 5186

South Asian (SAS) AF: 0.106 AC: 511 AN: 4828

European-Finnish (FIN) AF: 0.165 AC: 1745 AN: 10588

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8453 AN: 68026

Other (OTH) AF: 0.0863 AC: 182 AN: 2110

Alfa AF: 0.100 Hom.: 789

Bravo AF: 0.0801

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Parkinson disease 18, autosomal dominant, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.13
DANN	Benign	0.52
PhyloP100		-0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2293605; hg19: chr3-184044433;