19-17337612-A-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_032620.4(GTPBP3):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000171 in 1,172,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: GTPBP3 NM_032620.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000307319 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 38 pathogenic variants. Next in-frame start position is after 335 codons. Genomic position: 17341072. Lost 0.678 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032620.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTPBP3	NM_032620.4	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	NP_116009.2	Q969Y2-1
	GTPBP3	NM_133644.4		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 8	NP_598399.2	Q969Y2-2
	GTPBP3	NM_001128855.3		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	NP_001122327.1	Q969Y2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTPBP3	ENST00000324894.13	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000313818.7	Q969Y2-1
	GTPBP3	ENST00000600625.5	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000473150.1	Q969Y2-3
	GTPBP3	ENST00000600610.5	TSL:1	n.1A>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000469008.1	M0QXA1

Frequencies

GnomAD3 genomes Cov.: 32

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

African (AFR) AF: 0.00 AC: 0 AN: 23420

American (AMR) AF: 0.00 AC: 0 AN: 11054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15918

East Asian (EAS) AF: 0.0000359 AC: 1 AN: 27834

South Asian (SAS) AF: 0.00 AC: 0 AN: 36400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4790

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 963544

Other (OTH) AF: 0.00 AC: 0 AN: 47640

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.25
Sift	Benign	0.22	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.85
MutPred		0.98		Loss of disorder (P = 0.3353)
MVP		0.31
ClinPred		0.99	D
GERP RS		3.8
PromoterAI		0.087	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.37
Mutation Taster		=21/179	disease causing

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

Other links and lift over

dbSNP: rs1235128564; hg19: chr19-17448421;