3-184321181-C-T

Variant names:

• chr3-184321181-C-T
• rs4912537
• NM_198241.3:c.698-101C>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.698-101C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,528,668 control chromosomes in the GnomAD database, including 39,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3201 hom., cov: 32)
  • Exomes 𝑓: 0.23 (36395 hom.)
• Consequence: EIF4G1 NM_198241.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 8 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 3-184321181-C-T is Benign according to our data. Variant chr3-184321181-C-T is described in ClinVar as Benign. ClinVar VariationId is 1272665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4G1	NM_198241.3	MANE Select	c.698-101C>T		intron	N/A	NP_937884.2
	EIF4G1	NM_001194946.2		c.719-101C>T		intron	N/A	NP_001181875.2
	EIF4G1	NM_001194947.2		c.719-101C>T		intron	N/A	NP_001181876.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4G1	ENST00000346169.7	TSL:1 MANE Select	c.698-101C>T		intron	N/A	ENSP00000316879.5
	EIF4G1	ENST00000352767.7	TSL:1	c.719-101C>T		intron	N/A	ENSP00000338020.4
	EIF4G1	ENST00000382330.7	TSL:1	c.719-101C>T		intron	N/A	ENSP00000371767.3

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30367 AN: 151860 Hom.: 3200 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.0881

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.200

GnomAD4 exome AF: 0.227 AC: 312300 AN: 1376690 Hom.: 36395 Cov.: 22 AF XY: 0.225 AC XY: 155079 AN XY: 689132

African (AFR) AF: 0.145 AC: 4582 AN: 31682

American (AMR) AF: 0.186 AC: 8143 AN: 43858

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 4902 AN: 25400

East Asian (EAS) AF: 0.186 AC: 7266 AN: 39150

South Asian (SAS) AF: 0.152 AC: 12768 AN: 83728

European-Finnish (FIN) AF: 0.301 AC: 15694 AN: 52166

Middle Eastern (MID) AF: 0.135 AC: 737 AN: 5454

European-Non Finnish (NFE) AF: 0.237 AC: 246430 AN: 1037756

Other (OTH) AF: 0.205 AC: 11778 AN: 57496

GnomAD4 genome AF: 0.200 AC: 30379 AN: 151978 Hom.: 3201 Cov.: 32 AF XY: 0.201 AC XY: 14910 AN XY: 74278

African (AFR) AF: 0.147 AC: 6081 AN: 41458

American (AMR) AF: 0.170 AC: 2599 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 641 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1031 AN: 5172

South Asian (SAS) AF: 0.151 AC: 730 AN: 4824

European-Finnish (FIN) AF: 0.303 AC: 3192 AN: 10538

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15584 AN: 67950

Other (OTH) AF: 0.198 AC: 415 AN: 2098

Alfa AF: 0.218 Hom.: 15356

Bravo AF: 0.190

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

ClinVar submissions as Germline

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	0.074
DANN	Benign	0.32
PhyloP100		-1.3
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: rs4912537; hg19: chr3-184038969; COSMIC: COSV59991247; COSMIC: COSV59991247;