19-17337619-G-C

Position:

• chr19-17337619-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032620.4(GTPBP3):​c.8G>C​(p.Arg3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000341 in 1,172,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000034 (0 hom.)
• Consequence: GTPBP3 NM_032620.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37397462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTPBP3	NM_032620.4	c.8G>C	p.Arg3Pro	missense_variant	1/9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.8G>C	p.Arg3Pro	missense_variant	1/8		NP_598399.2
GTPBP3	NM_001128855.3	c.8G>C	p.Arg3Pro	missense_variant	1/9		NP_001122327.1
GTPBP3	NM_001195422.1	c.120-389G>C		intron_variant			NP_001182351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13	c.8G>C	p.Arg3Pro	missense_variant	1/9	1	NM_032620.4	ENSP00000313818.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000341 AC: 4 AN: 1172650 Hom.: 0 Cov.: 30 AF XY: 0.00000536 AC XY: 3 AN XY: 559844

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: 0.00000415

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2016

The R3P variant in the GTPBP3 gene has not been reported previously as a pathogenic variant, noras a benign variant, to our knowledge. However, a missense variant at this same codon (R3L) has beenreported previously in an individual with seizures, severe hypotonia, developmental delay and lacticacidosis, who was compound heterozygous for R3L and another variant (Kopajtich et al., 2014). TheR3P variant was not observed in approximately 6100 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. The R3P variant is a non-conservative amino acid substitution, which occurs at aposition that is conserved across species. In silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function. We interpret R3P as avariant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0010	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L;L;L
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.14
Sift	Uncertain	0.015	D;D;.
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.97	D;D;D
Vest4		0.47
MutPred		0.26		Gain of catalytic residue at R3 (P = 0.0806);Gain of catalytic residue at R3 (P = 0.0806);Gain of catalytic residue at R3 (P = 0.0806);
MVP		0.53
MPC		0.49
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.51
gMVP		0.62

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: rs1057518138; hg19: chr19-17448428;