rs879255373

Positions:

• chr20-63488306-CCGCCTTCTG-C
• chr20-63488306-CCGCCTTCTG-CCGCCTTCTGCGCCTTCTG

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM4 PP5 BS2

The NM_001958.5(EEF1A2):​c.1375_1383del​(p.Gln459_Ala461del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000368 in 1,385,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: EEF1A2 NM_001958.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.14

Genes affected

EEF1A2 (HGNC:3192): (eukaryotic translation elongation factor 1 alpha 2) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 2) is expressed in brain, heart and skeletal muscle, and the other isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas. This gene may be critical in the development of ovarian cancer. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001958.5.
• PP5: Variant 20-63488306-CCGCCTTCTG-C is Pathogenic according to our data. Variant chr20-63488306-CCGCCTTCTG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252597.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EEF1A2	NM_001958.5	c.1375_1383del	p.Gln459_Ala461del	inframe_deletion	8/8	ENST00000217182.6	NP_001949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEF1A2	ENST00000217182.6	c.1375_1383del	p.Gln459_Ala461del	inframe_deletion	8/8	1	NM_001958.5	ENSP00000217182	P1

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150518 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000380 AC: 47 AN: 1235298 Hom.: 0 AF XY: 0.0000379 AC XY: 23 AN XY: 607454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000479

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000309

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000433

Gnomad4 OTH exome AF: 0.0000204

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150630 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73522

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2017

A c.1375_1383delCAGAAGGCG variant that is likely pathogenic has been identified in the EEF1A2 gene. The c.1375_1383delCAGAAGGCG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 5,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1375_1383delCAGAAGGCG variant results in an in-frame deletion of three amino acids, denoted p.Gln459_Ala461del. This deletion occurs at a position that is conserved in mammals. However, the c.1375_1383delCAGAAGGCG variant is not predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. Therefore, based on the currently available information, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 19, 2015

- -

Developmental and epileptic encephalopathy, 33 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This variant, c.1375_1383del, results in the deletion of 3 amino acid(s) of the EEF1A2 protein (p.Gln459_Ala461del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with intellectual disability (PMID: 29784605). ClinVar contains an entry for this variant (Variation ID: 252597). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879255373; hg19: chr20-62119659;