20-63494805-G-C

Variant names:

• chr20-63494805-G-C
• NM_001958.5:c.621C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001958.5(EEF1A2):​c.621C>G​(p.Asn207Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EEF1A2 NM_001958.5 missense, splice_region
• Scores: Splicing: ADA: 0.00005365
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain tr-type G (size 237) in uniprot entity EF1A2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001958.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the EEF1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 4.8166 (above the threshold of 3.09). Trascript score misZ: 6.0564 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 33.
• BP4: Computational evidence support a benign effect (MetaRNN=0.116345346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EEF1A2	NM_001958.5	c.621C>G	p.Asn207Lys	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000217182.6	NP_001949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EEF1A2	ENST00000217182.6	c.621C>G	p.Asn207Lys	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_001958.5	ENSP00000217182.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456282 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.0
DANN	Benign	0.67
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.090
Sift	Benign	0.22	T
Sift4G	Benign	0.30	T
Polyphen		0.014	B
Vest4		0.30
MutPred		0.48		Gain of ubiquitination at N207 (P = 0.0162);
MVP		0.40
MPC		1.8
ClinPred		0.22	T
GERP RS		-2.4
Varity_R		0.18
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.15
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62126158;