rs1879244

Variant names:

• chr3-184328567-C-T
• rs1879244
• NM_198241.3:c.3954-64C>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.3954-64C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,612,336 control chromosomes in the GnomAD database, including 456,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49388 hom., cov: 31)
  • Exomes 𝑓: 0.75 (407544 hom.)
• Consequence: EIF4G1 NM_198241.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.132
• Publications: 9 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 3-184328567-C-T is Benign according to our data. Variant chr3-184328567-C-T is described in ClinVar as Benign. ClinVar VariationId is 1271491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.945 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.3954-64C>T		intron	N/A	NP_937884.2	Q04637-1
	EIF4G1	NM_001194946.2		c.3975-64C>T		intron	N/A	NP_001181875.2	Q04637-9
	EIF4G1	NM_001194947.2		c.3975-64C>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.3954-64C>T		intron	N/A	ENSP00000316879.5	Q04637-1
	EIF4G1	ENST00000352767.7	TSL:1	c.3975-64C>T		intron	N/A	ENSP00000338020.4	Q04637-9
	EIF4G1	ENST00000382330.7	TSL:1	c.3975-64C>T		intron	N/A	ENSP00000371767.3	Q04637-9

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121348 AN: 151998 Hom.: 49328 Cov.: 31

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.818

GnomAD4 exome AF: 0.745 AC: 1088202 AN: 1460220 Hom.: 407544 Cov.: 32 AF XY: 0.742 AC XY: 538847 AN XY: 726490

African (AFR) AF: 0.961 AC: 32157 AN: 33458

American (AMR) AF: 0.821 AC: 36700 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 21636 AN: 26122

East Asian (EAS) AF: 0.623 AC: 24706 AN: 39672

South Asian (SAS) AF: 0.668 AC: 57505 AN: 86084

European-Finnish (FIN) AF: 0.697 AC: 37128 AN: 53280

Middle Eastern (MID) AF: 0.818 AC: 4708 AN: 5758

European-Non Finnish (NFE) AF: 0.745 AC: 827850 AN: 1110810

Other (OTH) AF: 0.759 AC: 45812 AN: 60322

GnomAD4 genome AF: 0.798 AC: 121458 AN: 152116 Hom.: 49388 Cov.: 31 AF XY: 0.790 AC XY: 58723 AN XY: 74330

African (AFR) AF: 0.953 AC: 39576 AN: 41536

American (AMR) AF: 0.809 AC: 12361 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2863 AN: 3472

East Asian (EAS) AF: 0.635 AC: 3271 AN: 5152

South Asian (SAS) AF: 0.663 AC: 3201 AN: 4828

European-Finnish (FIN) AF: 0.688 AC: 7268 AN: 10564

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50506 AN: 67956

Other (OTH) AF: 0.810 AC: 1712 AN: 2114

Alfa AF: 0.773 Hom.: 6218

Bravo AF: 0.818

Asia WGS AF: 0.674 AC: 2347 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.84
DANN	Benign	0.24
PhyloP100		-0.13
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: rs1879244; hg19: chr3-184046355; COSMIC: COSV59993322; COSMIC: COSV59993322;