4-98881149-GAAA-GAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 4-98881149-GA-G is Benign according to our data. Variant chr4-98881149-GA-G is described in ClinVar as [Benign]. Clinvar id is 769289.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0155 (15562/1003252) while in subpopulation AMR AF = 0.0485 (1281/26404). AF 95% confidence interval is 0.0463. There are 1 homozygotes in GnomAdExome4. There are 8062 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5	c.540-8delT		splice_region_variant, intron_variant	Intron 6 of 6	ENST00000450253.7	NP_001959.1
EIF4E	NM_001130679.3	c.633-8delT		splice_region_variant, intron_variant	Intron 7 of 7		NP_001124151.1
EIF4E	NM_001331017.2	c.624-8delT		splice_region_variant, intron_variant	Intron 7 of 7		NP_001317946.1
EIF4E	NM_001130678.4	c.600-8delT		splice_region_variant, intron_variant	Intron 6 of 6		NP_001124150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7	c.540-8delT		splice_region_variant, intron_variant	Intron 6 of 6	1	NM_001968.5	ENSP00000389624.2

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 = 0.000000), 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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0505 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

Publications

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Other links and lift over

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