chr20-63488349-G-T

Variant names:

• chr20-63488349-G-T
• rs1453471749
• NM_001958.5:c.1341C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001958.5(EEF1A2):​c.1341C>A​(p.Gly447Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,316,560 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. Synonymous variant affecting the same amino acid position (i.e. G447G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: EEF1A2 NM_001958.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.423
• Publications: 0 publications found

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]

EEF1A2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 33

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP7: Synonymous conserved (PhyloP=-0.423 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001958.5. 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
	EEF1A2	NM_001958.5	MANE Select	c.1341C>A	p.Gly447Gly	synonymous	Exon 8 of 8	NP_001949.1	Q05639

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEF1A2	ENST00000217182.6	TSL:1 MANE Select	c.1341C>A	p.Gly447Gly	synonymous	Exon 8 of 8	ENSP00000217182.3	Q05639
	EEF1A2	ENST00000298049.13	TSL:1	c.1341C>A	p.Gly447Gly	synonymous	Exon 8 of 9	ENSP00000298049.9	A0A2U3TZH3
	EEF1A2	ENST00000706949.1		c.1341C>A	p.Gly447Gly	synonymous	Exon 8 of 9	ENSP00000516669.1	A0A9L9PYI8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000228 AC: 3 AN: 1316560 Hom.: 0 Cov.: 33 AF XY: 0.00000308 AC XY: 2 AN XY: 649238

⚠️ 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: 26562

American (AMR) AF: 0.00 AC: 0 AN: 26092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23018

East Asian (EAS) AF: 0.0000360 AC: 1 AN: 27810

South Asian (SAS) AF: 0.00 AC: 0 AN: 72388

European-Finnish (FIN) AF: 0.0000254 AC: 1 AN: 39442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5042

European-Non Finnish (NFE) AF: 9.59e-7 AC: 1 AN: 1042254

Other (OTH) AF: 0.00 AC: 0 AN: 53952

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0965794), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.3
DANN	Benign	0.96
PhyloP100		-0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1453471749; hg19: chr20-62119702;