3-128153621-G-T

Variant names:

• chr3-128153621-G-T
• rs1164834792
• NM_021937.5:c.114G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021937.5(EEFSEC):​c.114G>T​(p.Lys38Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 1,444,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: EEFSEC NM_021937.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

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]

RUVBL1 (HGNC:10474): (RuvB like AAA ATPase 1) This gene encodes a protein that has both DNA-dependent ATPase and DNA helicase activities and belongs to the ATPases associated with diverse cellular activities (AAA+) protein family. The encoded protein associates with several multisubunit transcriptional complexes and with protein complexes involved in both ATP-dependent remodeling and histone modification. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EEFSEC	NM_021937.5	c.114G>T	p.Lys38Asn	missense_variant	Exon 1 of 7	ENST00000254730.11	NP_068756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EEFSEC	ENST00000254730.11	c.114G>T	p.Lys38Asn	missense_variant	Exon 1 of 7	1	NM_021937.5	ENSP00000254730.5
EEFSEC	ENST00000483457.1	c.114G>T	p.Lys38Asn	missense_variant	Exon 1 of 5	5		ENSP00000417660.1
RUVBL1	ENST00000464873.5	c.-458C>A		5_prime_UTR_variant	Exon 1 of 10	2		ENSP00000420738.1
EEFSEC	ENST00000484438.1	n.-47G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1444740 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000231

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.114G>T (p.K38N) alteration is located in exon 1 (coding exon 1) of the EEFSEC gene. This alteration results from a G to T substitution at nucleotide position 114, causing the lysine (K) at amino acid position 38 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.74	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.099
MutPred		0.56		Loss of ubiquitination at K38 (P = 0.0043);Loss of ubiquitination at K38 (P = 0.0043);
MVP		0.72
MPC		2.0
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.86
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1164834792; hg19: chr3-127872464;