rs4912537

Variant names:

• chr3-184321181-C-A
• rs4912537
• NM_198241.3:c.698-101C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-184321181-C-A
• chr3-184321181-C-G
• chr3-184321181-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198241.3(EIF4G1):​c.698-101C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,378,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: EIF4G1 NM_198241.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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>A		intron	N/A	NP_937884.2
	EIF4G1	NM_001194946.2		c.719-101C>A		intron	N/A	NP_001181875.2
	EIF4G1	NM_001194947.2		c.719-101C>A		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>A		intron	N/A	ENSP00000316879.5
	EIF4G1	ENST00000352767.7	TSL:1	c.719-101C>A		intron	N/A	ENSP00000338020.4
	EIF4G1	ENST00000382330.7	TSL:1	c.719-101C>A		intron	N/A	ENSP00000371767.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1378210 Hom.: 0 Cov.: 22 AF XY: 0.00000145 AC XY: 1 AN XY: 689848

⚠️ 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: 31702

American (AMR) AF: 0.00 AC: 0 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25404

East Asian (EAS) AF: 0.00 AC: 0 AN: 39160

South Asian (SAS) AF: 0.00 AC: 0 AN: 83764

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1039098

Other (OTH) AF: 0.00 AC: 0 AN: 57542

⚠️ 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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.029
DANN	Benign	0.42
PhyloP100		-1.3

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;