4-98881149-GAAA-GAA

Variant names:

• chr4-98881149-GA-G
• rs374891583
• NM_001968.5:c.540-8delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001968.5(EIF4E):​c.540-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,125,276 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.016 (1 hom.)
• Consequence: EIF4E NM_001968.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.94
• Publications: 0 publications found

Genes affected

EIF4E (HGNC:3287): (eukaryotic translation initiation factor 4E) The protein encoded by this gene is a component of the eukaryotic translation initiation factor 4F complex, which recognizes the 7-methylguanosine cap structure at the 5' end of messenger RNAs. The encoded protein aids in translation initiation by recruiting ribosomes to the 5'-cap structure. Association of this protein with the 4F complex is the rate-limiting step in translation initiation. This gene acts as a proto-oncogene, and its expression and activation is associated with transformation and tumorigenesis. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

EIF4E Gene-Disease associations (from GenCC):

• autism, susceptibility to, 19

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0463) population. However there is too low homozygotes in high coverage region: (expected more than 54, got 1).
• BP6: Variant 4-98881149-GA-G is Benign according to our data. Variant chr4-98881149-GA-G is described in ClinVar as Benign. ClinVar VariationId is 769289.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001968.5. 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
	EIF4E	NM_001968.5	MANE Select	c.540-8delT		splice_region intron	N/A	NP_001959.1	P06730-1
	EIF4E	NM_001130679.3		c.633-8delT		splice_region intron	N/A	NP_001124151.1	P06730-2
	EIF4E	NM_001331017.2		c.624-8delT		splice_region intron	N/A	NP_001317946.1	D6RBW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4E	ENST00000450253.7	TSL:1 MANE Select	c.540-8delT		splice_region intron	N/A	ENSP00000389624.2	P06730-1
	EIF4E	ENST00000280892.10	TSL:1	c.600-8delT		splice_region intron	N/A	ENSP00000280892.6	P06730-3
	EIF4E	ENST00000505992.1	TSL:5	c.633-8delT		splice_region intron	N/A	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes AF: 0.000656 AC: 80 AN: 122002 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000163

Gnomad ASJ AF: 0.00304

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000500

Gnomad FIN AF: 0.00285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000708

Gnomad OTH AF: 0.00175

GnomAD2 exomes AF: 0.0607 AC: 5633 AN: 92850 AF XY: 0.0613

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.0823

Gnomad ASJ exome AF: 0.0629

Gnomad EAS exome AF: 0.0598

Gnomad FIN exome AF: 0.0319

Gnomad NFE exome AF: 0.0681

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0155 AC: 15562 AN: 1003252 Hom.: 1 Cov.: 31 AF XY: 0.0163 AC XY: 8062 AN XY: 494464

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0125 AC: 308 AN: 24570

American (AMR) AF: 0.0485 AC: 1281 AN: 26404

Ashkenazi Jewish (ASJ) AF: 0.0361 AC: 566 AN: 15658

East Asian (EAS) AF: 0.0351 AC: 793 AN: 22622

South Asian (SAS) AF: 0.0243 AC: 1272 AN: 52450

European-Finnish (FIN) AF: 0.0337 AC: 1072 AN: 31776

Middle Eastern (MID) AF: 0.0173 AC: 73 AN: 4214

European-Non Finnish (NFE) AF: 0.0119 AC: 9312 AN: 785324

Other (OTH) AF: 0.0220 AC: 885 AN: 40234

⚠️ 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 AF: 0.000656 AC: 80 AN: 122024 Hom.: 0 Cov.: 31 AF XY: 0.000768 AC XY: 45 AN XY: 58618

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000153 AC: 5 AN: 32608

American (AMR) AF: 0.000162 AC: 2 AN: 12308

Ashkenazi Jewish (ASJ) AF: 0.00304 AC: 9 AN: 2964

East Asian (EAS) AF: 0.00 AC: 0 AN: 4306

South Asian (SAS) AF: 0.000502 AC: 2 AN: 3986

European-Finnish (FIN) AF: 0.00285 AC: 19 AN: 6672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.000708 AC: 40 AN: 56492

Other (OTH) AF: 0.00174 AC: 3 AN: 1724

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0505 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

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: rs374891583; hg19: chr4-99802300; COSMIC: COSV55186256;