19-17337613-T-C

Variant names:

• chr19-17337613-T-C
• rs1019249439
• NM_032620.4:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_032620.4(GTPBP3):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,171,330 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• 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 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 39 pathogenic variants. Next in-frame start position is after 335 codons. Genomic position: 17341072. Lost 0.678 part of the original CDS.
• PS1: Another start lost variant in NM_032620.4 (GTPBP3) was described as [Pathogenic] in ClinVar as 488854
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-17337613-T-C is Pathogenic according to our data. Variant chr19-17337613-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3685514.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTPBP3	NM_032620.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 8		NP_598399.2
GTPBP3	NM_001128855.3	c.2T>C	p.Met1?	start_lost	Exon 1 of 9		NP_001122327.1
GTPBP3	NM_001195422.1	c.120-395T>C		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.2T>C	p.Met1?	start_lost	Exon 1 of 9	1	NM_032620.4	ENSP00000313818.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000256 AC: 3 AN: 1171330 Hom.: 0 Cov.: 30 AF XY: 0.00000179 AC XY: 1 AN XY: 559074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000906

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: 0.00000208

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

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the GTPBP3 mRNA. The next in-frame methionine is located at codon 367. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GTPBP3-related conditions. This variant disrupts a region of the GTPBP3 protein in which other variant(s) (p.Gln262Pro) have been determined to be pathogenic (PMID: 34276756, 36980825). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.60	P;P;P
Vest4		0.83
MutPred		0.98		Loss of stability (P = 0.008);Loss of stability (P = 0.008);Loss of stability (P = 0.008);
MVP		0.45
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.56

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;