19-17337612-A-G

Variant names:

• chr19-17337612-A-G
• rs1235128564
• NM_032620.4:c.1A>G

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.1A>G​(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 0.00000227 in 1,324,424 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: GTPBP3 NM_032620.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.57

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 19-17337612-A-G is Pathogenic according to our data. Variant chr19-17337612-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3676155.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.1A>G	p.Met1?	start_lost	Exon 1 of 9	ENST00000324894.13	NP_116009.2
GTPBP3	NM_133644.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 8		NP_598399.2
GTPBP3	NM_001128855.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 9		NP_001122327.1
GTPBP3	NM_001195422.1	c.120-396A>G		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.1A>G	p.Met1?	start_lost	Exon 1 of 9	1	NM_032620.4	ENSP00000313818.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000171 AC: 2 AN: 1172294 Hom.: 0 Cov.: 30 AF XY: 0.00000357 AC XY: 2 AN XY: 559654

Gnomad4 AFR exome AF: 0.0000427

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: 0.0000210

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 09, 2024

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	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T;.;.
Eigen	Benign	-0.031
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.67	N;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.019	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.13	B;P;B
Vest4		0.71
MutPred		0.98		Loss of disorder (P = 0.053);Loss of disorder (P = 0.053);Loss of disorder (P = 0.053);
MVP		0.35
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1235128564; hg19: chr19-17448421;