chr4-44678680-A-G

Position:

chr4-44678680-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000281543.6(GUF1):c.58A>G(p.Thr20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000726 in 1,500,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T20T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GUF1
ENST00000281543.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: -2.03

Variant links:

Genes affected

GUF1 (HGNC:25799): (GTP binding elongation factor GUF1) This gene encodes a GTPase that triggers back-translocation of the elongating ribosome during mitochondrial protein synthesis. The protein contains a highly conserved C-terminal domain not found in other GTPases that facilitates tRNA binding. The encoded protein is thought to prevent misincorporation of amino acids in stressful, suboptimal conditions. An allelic variant in this gene has been associated with early infantile epileptic encephalopathy-40. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

GUF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008924484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUF1	NM_021927.3 linkuse as main transcript	c.58A>G	p.Thr20Ala	missense_variant	1/17	ENST00000281543.6	NP_068746.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GUF1	ENST00000281543.6 linkuse as main transcript	c.58A>G	p.Thr20Ala	missense_variant	1/17	1	NM_021927.3	ENSP00000281543	P1
GUF1	ENST00000513775.1 linkuse as main transcript	c.58A>G	p.Thr20Ala	missense_variant, NMD_transcript_variant	1/9	1		ENSP00000422681
GUF1	ENST00000506793.5 linkuse as main transcript	n.159+95A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000533

AC:

AN:

131440

Hom.:

AF XY:

0.0000523

AC XY:

AN XY:

76416

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000222

AC:

AN:

1348808

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

667130

show subpopulations

Gnomad4 AFR exome

AF:

0.000917

Gnomad4 AMR exome

AF:

0.0000515

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:

0.0000901

GnomAD4 genome

AF:

0.000519

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00174

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000442

ESP6500AA

AF:

0.00101

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000928

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 20 of the GUF1 protein (p.Thr20Ala). This variant is present in population databases (rs368489353, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with GUF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1350268). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

GUF1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.0010

DANN

Benign

0.88

DEOGEN2

Benign

0.053

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.32

M_CAP

Benign

0.012

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.31

REVEL

Benign

0.067

Sift

Benign

0.42

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MVP

0.20

MPC

0.059

ClinPred

0.036

GERP RS

-7.1

Varity_R

0.035

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over