3-128153508-A-G

Variant names:

• chr3-128153508-A-G
• rs1009397010
• NM_021937.5:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Supporting PM2 PP5

The NM_021937.5(EEFSEC):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: EEFSEC NM_021937.5 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.15

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 4 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 113 codons. Genomic position: 128246856. Lost 0.188 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-128153508-A-G is Pathogenic according to our data. Variant chr3-128153508-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3764735.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EEFSEC	NM_021937.5	c.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 1 of 7	1	NM_021937.5	ENSP00000254730.5
EEFSEC	ENST00000483457.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	5		ENSP00000417660.1
RUVBL1	ENST00000464873.5	c.-345T>C		5_prime_UTR_variant	Exon 1 of 10	2		ENSP00000420738.1
EEFSEC	ENST00000484438.1	n.-160A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345654 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 663376

Gnomad4 AFR exome AF: 0.0000371

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain abnormalities Pathogenic:1

Feb 25, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.098	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.42	N
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.077	B;B
Vest4		0.45
MutPred		0.98		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.45
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.72
gMVP		0.55

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: rs1009397010; hg19: chr3-127872351;