rs730880255

Variant names:

• chr19-17338626-A-T
• rs730880255
• NM_032620.4:c.476A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_032620.4(GTPBP3):​c.476A>T​(p.Glu159Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GTPBP3 NM_032620.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.62

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 19-17338626-A-T is Pathogenic according to our data. Variant chr19-17338626-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 180616.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-17338626-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTPBP3	NM_032620.4	c.476A>T	p.Glu159Val	missense_variant	Exon 4 of 9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.476A>T	p.Glu159Val	missense_variant	Exon 4 of 8		NP_598399.2
GTPBP3	NM_001195422.1	c.542A>T	p.Glu181Val	missense_variant	Exon 4 of 9		NP_001182351.1
GTPBP3	NM_001128855.3	c.476A>T	p.Glu159Val	missense_variant	Exon 4 of 9		NP_001122327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13	c.476A>T	p.Glu159Val	missense_variant	Exon 4 of 9	1	NM_032620.4	ENSP00000313818.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined oxidative phosphorylation defect type 23 Pathogenic:1

Dec 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	.;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.072	D
MutationAssessor	Pathogenic	4.5	.;H;H;H
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.8	D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.96
MutPred		0.78		.;Loss of disorder (P = 0.0433);Loss of disorder (P = 0.0433);Loss of disorder (P = 0.0433);
MVP		0.80
MPC		1.1
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs730880255; hg19: chr19-17449435;