5-138518814-C-T

Variant names:

• chr5-138518814-C-T
• rs1178912679
• NM_004730.4:c.140G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004730.4(ETF1):​c.140G>A​(p.Arg47Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ETF1 NM_004730.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

Genes affected

ETF1 (HGNC:3477): (eukaryotic translation termination factor 1) This gene encodes a class-1 polypeptide chain release factor. The encoded protein plays an essential role in directing termination of mRNA translation from the termination codons UAA, UAG and UGA. This protein is a component of the SURF complex which promotes degradation of prematurely terminated mRNAs via the mechanism of nonsense-mediated mRNA decay (NMD). Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 6, 7, and X. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
ETF1	NM_004730.4	c.140G>A	p.Arg47Gln	missense_variant	Exon 3 of 11	ENST00000360541.10	NP_004721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETF1	ENST00000360541.10	c.140G>A	p.Arg47Gln	missense_variant	Exon 3 of 11	1	NM_004730.4	ENSP00000353741.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140G>A (p.R47Q) alteration is located in exon 3 (coding exon 2) of the ETF1 gene. This alteration results from a G to A substitution at nucleotide position 140, causing the arginine (R) at amino acid position 47 to be replaced by a glutamine (Q). 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	0.89
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;.;T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	.;L;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;N;N;.;N
REVEL	Benign	0.26
Sift	Benign	0.15	T;T;T;.;T
Sift4G	Benign	0.21	T;T;T;.;.
Polyphen		0.34, 0.67	.;B;P;.;.
Vest4		0.73
MutPred		0.51		.;Gain of ubiquitination at K42 (P = 0.052);.;.;.;
MVP		0.83
MPC		2.0
ClinPred		0.86	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.91
Mutation Taster		=6/94	disease causing

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: rs1178912679; hg19: chr5-137854503; COSMIC: COSV100860307; COSMIC: COSV100860307;