3-128262219-A-G

Variant names:

• chr3-128262219-A-G
• rs763279916
• NM_021937.5:c.616A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021937.5(EEFSEC):​c.616A>G​(p.Ile206Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I206T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EEFSEC NM_021937.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.37
• Publications: 1 publications found

Genes affected

EEFSEC (HGNC:24614): (eukaryotic elongation factor, selenocysteine-tRNA specific) Predicted to enable translation elongation factor activity. Predicted to be involved in selenocysteine incorporation. Predicted to be located in cytoplasm and nucleus. Predicted to be part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

EEFSEC Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with progressive spasticity and brain abnormalities

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2833181).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021937.5. 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
	EEFSEC	NM_021937.5	MANE Select	c.616A>G	p.Ile206Val	missense	Exon 3 of 7	NP_068756.2	P57772-1
	EEFSEC	NM_001437809.1		c.616A>G	p.Ile206Val	missense	Exon 3 of 8	NP_001424738.1
	EEFSEC	NM_001437810.1		c.616A>G	p.Ile206Val	missense	Exon 3 of 7	NP_001424739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEFSEC	ENST00000254730.11	TSL:1 MANE Select	c.616A>G	p.Ile206Val	missense	Exon 3 of 7	ENSP00000254730.5	P57772-1
	EEFSEC	ENST00000868107.1		c.616A>G	p.Ile206Val	missense	Exon 3 of 8	ENSP00000538166.1
	EEFSEC	ENST00000868109.1		c.616A>G	p.Ile206Val	missense	Exon 3 of 8	ENSP00000538168.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461256 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726940

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111458

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.063
Eigen_PC	Benign	0.080
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.27
Sift	Benign	0.33	T
Sift4G	Benign	0.56	T
Polyphen		0.28	B
Vest4		0.54
MVP		0.58
MPC		0.11
ClinPred		0.55	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.21
Mutation Taster		=63/37	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: rs763279916; hg19: chr3-127981062;