rs886037734

Positions:

• chr19-17341599-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_032620.4(GTPBP3):​c.1375G>A​(p.Glu459Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,608 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GTPBP3 NM_032620.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.89

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• PP5: Variant 19-17341599-G-A is Pathogenic according to our data. Variant chr19-17341599-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 180615.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-17341599-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTPBP3	NM_032620.4	c.1375G>A	p.Glu459Lys	missense_variant	9/9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.1471G>A	p.Glu491Lys	missense_variant	8/8		NP_598399.2
GTPBP3	NM_001195422.1	c.1441G>A	p.Glu481Lys	missense_variant	9/9		NP_001182351.1
GTPBP3	NM_001128855.3	c.1312G>A	p.Glu438Lys	missense_variant	9/9		NP_001122327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13	c.1375G>A	p.Glu459Lys	missense_variant	9/9	1	NM_032620.4	ENSP00000313818.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461608 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727094

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined oxidative phosphorylation defect type 23 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 04, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	.;D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	4.3	.;H;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;D;D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0070	D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;D;D;D
Vest4		0.70
MutPred		0.55		.;Gain of MoRF binding (P = 0.0013);.;.;
MVP		0.81
MPC		1.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.80

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

Other links and lift over

dbSNP: rs886037734; hg19: chr19-17452408; COSMIC: COSV61414206; COSMIC: COSV61414206;