Genetic Variant GTPBP3:p.Gly4Trp (chr19-17337621-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032620.4(GTPBP3):c.10G>T(p.Gly4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000851 in 1,174,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

GTPBP3
NM_032620.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.228

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation defect type 23
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

GTPBP3 links:

ENSG00000307319 (HGNC:):

ENSG00000307319 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1777181).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032620.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GTPBP3	NM_032620.4	MANE Select	c.10G>T	p.Gly4Trp	missense	Exon 1 of 9	NP_116009.2	Q969Y2-1
GTPBP3	NM_133644.4		c.10G>T	p.Gly4Trp	missense	Exon 1 of 8	NP_598399.2	Q969Y2-2
GTPBP3	NM_001128855.3		c.10G>T	p.Gly4Trp	missense	Exon 1 of 9	NP_001122327.1	Q969Y2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GTPBP3	ENST00000324894.13	TSL:1 MANE Select	c.10G>T	p.Gly4Trp	missense	Exon 1 of 9	ENSP00000313818.7	Q969Y2-1
GTPBP3	ENST00000600625.5	TSL:1	c.10G>T	p.Gly4Trp	missense	Exon 1 of 9	ENSP00000473150.1	Q969Y2-3
GTPBP3	ENST00000600610.5	TSL:1	n.10G>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000469008.1	M0QXA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.51e-7

AC:

AN:

1174572

Hom.:

Cov.:

AF XY:

0.00000178

AC XY:

AN XY:

560786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23450

American (AMR)

AF:

0.00

AC:

AN:

11034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15986

East Asian (EAS)

AF:

0.00

AC:

AN:

27846

South Asian (SAS)

AF:

0.00

AC:

AN:

36940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4800

European-Non Finnish (NFE)

AF:

0.00000104

AC:

AN:

964966

Other (OTH)

AF:

0.00

AC:

AN:

47784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.74

M_CAP

Benign

0.010

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

0.23

PROVEAN

Benign

-1.4

REVEL

Benign

0.069

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.028

Polyphen

0.99

Vest4

0.30

MutPred

0.45

Loss of disorder (P = 0.0048)

MVP

0.40

MPC

0.36

ClinPred

0.78

GERP RS

1.2

PromoterAI

-0.0070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.10

gMVP

0.49

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over