19-17337640-C-T

Variant names:

• chr19-17337640-C-T
• NM_032620.4:c.29C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032620.4(GTPBP3):​c.29C>T​(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GTPBP3 NM_032620.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.168

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07839358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTPBP3	NM_032620.4	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 8		NP_598399.2
GTPBP3	NM_001128855.3	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 9		NP_001122327.1
GTPBP3	NM_001195422.1	c.120-368C>T		intron_variant	Intron 1 of 8		NP_001182351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 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: 1182864 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 565376

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with GTPBP3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the GTPBP3 protein (p.Ala10Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N
PROVEAN	Benign	-0.27	N;N;.
REVEL	Benign	0.013
Sift	Benign	0.047	D;D;.
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.11	B;B;B
Vest4		0.25
MutPred		0.35		Loss of disorder (P = 0.0034);Loss of disorder (P = 0.0034);Loss of disorder (P = 0.0034);
MVP		0.24
MPC		0.29
ClinPred		0.095	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.46

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.

Other links and lift over

hg19: chr19-17448449;