dbSNP rs372174278: GTPBP3:p.Ala322Thr (chr19-17339589-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_032620.4(GTPBP3):c.964G>A(p.Ala322Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A322P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GTPBP3
NM_032620.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-17339589-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTPBP3	NM_032620.4 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 7 of 9	ENST00000324894.13	NP_116009.2	Q969Y2-1
GTPBP3	NM_133644.4 link	c.1060G>A	p.Ala354Thr	missense_variant	Exon 6 of 8		NP_598399.2	Q969Y2-2B7Z563
GTPBP3	NM_001195422.1 link	c.1030G>A	p.Ala344Thr	missense_variant	Exon 7 of 9		NP_001182351.1	Q969Y2-4B7Z563
GTPBP3	NM_001128855.3 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 7 of 9		NP_001122327.1	Q969Y2-3B7Z563

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 7 of 9	1	NM_032620.4	ENSP00000313818.7		Q969Y2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453048

Hom.:

Cov.:

AF XY:

0.00000138

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

.;T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

.;L;.;L

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.5

D;D;D;.

REVEL

Uncertain

0.37

Sift

Benign

0.052

T;T;T;.

Sift4G

Benign

0.098

T;T;T;T

Polyphen

1.0, 1.0

.;D;D;D

Vest4

0.78

MutPred

0.62

.;Gain of phosphorylation at A322 (P = 0.0117);.;Gain of phosphorylation at A322 (P = 0.0117);

MVP

0.66

MPC

0.96

ClinPred

0.98

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.76

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over