19-17337646-C-A

Position:

• chr19-17337646-C-A

Variant summary

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

The NM_032620.4(GTPBP3):​c.35C>A​(p.Ala12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000846 in 1,181,446 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 8.5e-7 (0 hom.)
• Consequence: GTPBP3 NM_032620.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13295543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTPBP3	NM_032620.4	c.35C>A	p.Ala12Glu	missense_variant	1/9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.35C>A	p.Ala12Glu	missense_variant	1/8		NP_598399.2
GTPBP3	NM_001128855.3	c.35C>A	p.Ala12Glu	missense_variant	1/9		NP_001122327.1
GTPBP3	NM_001195422.1	c.120-362C>A		intron_variant			NP_001182351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13	c.35C>A	p.Ala12Glu	missense_variant	1/9	1	NM_032620.4	ENSP00000313818.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.46e-7 AC: 1 AN: 1181446 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 564622

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: 0.00000103

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2021

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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with glutamic acid at codon 12 of the GTPBP3 protein (p.Ala12Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;N;N
PROVEAN	Benign	-0.89	N;N;.
REVEL	Benign	0.15
Sift	Uncertain	0.023	D;D;.
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.024	B;B;B
Vest4		0.37
MutPred		0.22		Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);
MVP		0.36
MPC		0.35
ClinPred		0.70	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr19-17448455;