19-17337613-T-A

Position:

• chr19-17337613-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032620.4(GTPBP3):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GTPBP3 NM_032620.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.24

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-17337613-T-A is Pathogenic according to our data. Variant chr19-17337613-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 488854.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTPBP3	NM_032620.4	c.2T>A	p.Met1?	start_lost	1/9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.2T>A	p.Met1?	start_lost	1/8		NP_598399.2
GTPBP3	NM_001128855.3	c.2T>A	p.Met1?	start_lost	1/9		NP_001122327.1
GTPBP3	NM_001195422.1	c.120-395T>A		intron_variant			NP_001182351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13	c.2T>A	p.Met1?	start_lost	1/9	1	NM_032620.4	ENSP00000313818.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1171330 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 559074

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2015

The c.2T>A pathogenic variant in the GTPBP3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. As this pathogenic variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. The c.2T>A variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2T>A as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.035	T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.60	P;P;P
Vest4		0.88
MutPred		0.97		Loss of stability (P = 0.0063);Loss of stability (P = 0.0063);Loss of stability (P = 0.0063);
MVP		0.46
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.71

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: rs1019249439; hg19: chr19-17448422;