4-44686523-C-T

Position:

chr4-44686523-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001345867.2(GUF1):c.-225C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,610,132 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 16 hom. )

Consequence

GUF1
NM_001345867.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.805

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:

GNPDA2 (HGNC:21526): (glucosamine-6-phosphate deaminase 2) The protein encoded by this gene is an allosteric enzyme that catalyzes the reversible reaction converting D-glucosamine-6-phosphate into D-fructose-6-phosphate and ammonium. Variations of this gene have been reported to be associated with influencing body mass index and susceptibility to obesity. A pseudogene of this gene is located on chromosome 9. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

GNPDA2 links:

GUF1 (HGNC:):

GUF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038073063).

BP6

Variant 4-44686523-C-T is Benign according to our data. Variant chr4-44686523-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445372.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUF1	NM_021927.3 linkuse as main transcript	c.748C>T	p.Arg250Cys	missense_variant	8/17	ENST00000281543.6	NP_068746.2	Q8N442

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUF1	ENST00000281543.6 linkuse as main transcript	c.748C>T	p.Arg250Cys	missense_variant	8/17	1	NM_021927.3	ENSP00000281543.5		Q8N442

Frequencies

GnomAD3 genomes

AF:

0.00307

AC:

466

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000991

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00441

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00505

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00234

AC:

585

AN:

250528

Hom.:

AF XY:

0.00231

AC XY:

313

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000360

Gnomad FIN exome

AF:

0.000742

Gnomad NFE exome

AF:

0.00403

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00397

AC:

5784

AN:

1458146

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

2776

AN XY:

725506

show subpopulations

Gnomad4 AFR exome

AF:

0.000540

Gnomad4 AMR exome

AF:

0.00249

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000314

Gnomad4 FIN exome

AF:

0.000844

Gnomad4 NFE exome

AF:

0.00484

Gnomad4 OTH exome

AF:

0.00347

GnomAD4 genome

AF:

0.00307

AC:

466

AN:

151986

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

222

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.000988

Gnomad4 AMR

AF:

0.00440

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000755

Gnomad4 NFE

AF:

0.00505

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00350

Hom.:

Bravo

AF:

0.00309

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00454

AC:

ExAC

AF:

0.00227

AC:

276

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GUF1: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -

GUF1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2019

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

0.10

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.035

Sift

Benign

0.077

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.11

MVP

0.27

MPC

0.078

ClinPred

0.015

GERP RS

3.3

Varity_R

0.087

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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