rs372174278

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_032620.4(GTPBP3):c.964G>C(p.Ala322Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,605,234 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

GTPBP3
NM_032620.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 8.55

Variant links:

Genes affected

GTPBP3 (HGNC:14880): (GTP binding protein 3, mitochondrial) This locus encodes a GTP-binding protein. The encoded protein is localized to the mitochondria and may play a role in mitochondrial tRNA modification. Polymorphisms at this locus may be associated with severity of aminoglycoside-induced deafness, a disease associated with a mutation in the 12S rRNA. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Sep 2010]

GTPBP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain TrmE-type G (size 167) in uniprot entity GTPB3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_032620.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

PP5

Variant 19-17339589-G-C is Pathogenic according to our data. Variant chr19-17339589-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180617.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr19-17339589-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTPBP3	NM_032620.4 link	c.964G>C	p.Ala322Pro	missense_variant	7/9	ENST00000324894.13	NP_116009.2	Q969Y2-1
GTPBP3	NM_133644.4 link	c.1060G>C	p.Ala354Pro	missense_variant	6/8		NP_598399.2	Q969Y2-2B7Z563
GTPBP3	NM_001195422.1 link	c.1030G>C	p.Ala344Pro	missense_variant	7/9		NP_001182351.1	Q969Y2-4B7Z563
GTPBP3	NM_001128855.3 link	c.964G>C	p.Ala322Pro	missense_variant	7/9		NP_001122327.1	Q969Y2-3B7Z563

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13 link	c.964G>C	p.Ala322Pro	missense_variant	7/9	1	NM_032620.4	ENSP00000313818.7		Q969Y2-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000117

AC:

AN:

231342

Hom.:

AF XY:

0.000173

AC XY:

AN XY:

126802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000251

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000915

AC:

133

AN:

1453048

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

722922

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000113

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000134

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 23

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 04, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 12, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5,BP6. -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2022	Published functional studies demonstrate a damaging effect (reduction of GTPase activity and impaired tRNA modification) (Peng et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as A322P; This variant is associated with the following publications: (PMID: 26832457, 34426522, 33619562, 25434004) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 22, 2022	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 354 of the GTPBP3 protein (p.Ala354Pro). This variant is present in population databases (rs372174278, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 25434004). This variant is also known as p.Ala322Pro. ClinVar contains an entry for this variant (Variation ID: 180617). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GTPBP3 function (PMID: 33619562). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

.;D;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

3.0

.;M;.;M

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.7

D;D;D;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.0030

D;D;D;.

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.93

MVP

0.73

MPC

1.1

ClinPred

0.88

GERP RS

5.0

Varity_R

0.97

gMVP

0.94

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