NM_021937.5:c.443T>C

Variant names:

• chr3-128246962-T-C
• rs777862851
• NM_021937.5:c.443T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_021937.5(EEFSEC):​c.443T>C​(p.Ile148Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,940 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I148V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: EEFSEC NM_021937.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.879
• Publications: 0 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: 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 (MetaRNN=0.31091666).
• BP6: Variant 3-128246962-T-C is Benign according to our data. Variant chr3-128246962-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3506802.Status of the report is criteria_provided_single_submitter, 1 stars.

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.443T>C	p.Ile148Thr	missense	Exon 2 of 7	NP_068756.2	P57772-1
	EEFSEC	NM_001437809.1		c.443T>C	p.Ile148Thr	missense	Exon 2 of 8	NP_001424738.1
	EEFSEC	NM_001437810.1		c.443T>C	p.Ile148Thr	missense	Exon 2 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.443T>C	p.Ile148Thr	missense	Exon 2 of 7	ENSP00000254730.5	P57772-1
	EEFSEC	ENST00000868107.1		c.443T>C	p.Ile148Thr	missense	Exon 2 of 8	ENSP00000538166.1
	EEFSEC	ENST00000868109.1		c.443T>C	p.Ile148Thr	missense	Exon 2 of 8	ENSP00000538168.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152046 Hom.: 0 Cov.: 33

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: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251060 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74240

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10574

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

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

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.056
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.55	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.88
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Benign	0.094	T
Sift4G	Benign	0.15	T
Polyphen		0.016	B
Vest4		0.46
MutPred		0.57		Loss of stability (P = 0)
MVP		0.58
MPC		1.0
ClinPred		0.13	T
GERP RS		-0.41
Varity_R		0.18
gMVP		0.63
Mutation Taster		=86/14	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: rs777862851; hg19: chr3-127965805;