19-17337619-G-T

Variant names:

• chr19-17337619-G-T
• rs1057518138
• NM_032620.4:c.8G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032620.4(GTPBP3):​c.8G>T​(p.Arg3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,324,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GTPBP3 NM_032620.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.14
• Publications: 8 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19254532).

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.8G>T	p.Arg3Leu	missense	Exon 1 of 9	NP_116009.2	Q969Y2-1
	GTPBP3	NM_133644.4		c.8G>T	p.Arg3Leu	missense	Exon 1 of 8	NP_598399.2	Q969Y2-2
	GTPBP3	NM_001128855.3		c.8G>T	p.Arg3Leu	missense	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.8G>T	p.Arg3Leu	missense	Exon 1 of 9	ENSP00000313818.7	Q969Y2-1
	GTPBP3	ENST00000600625.5	TSL:1	c.8G>T	p.Arg3Leu	missense	Exon 1 of 9	ENSP00000473150.1	Q969Y2-3
	GTPBP3	ENST00000600610.5	TSL:1	n.8G>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000469008.1	M0QXA1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 29 AN: 1172650 Hom.: 0 Cov.: 30 AF XY: 0.0000304 AC XY: 17 AN XY: 559844

African (AFR) AF: 0.00 AC: 0 AN: 23434

American (AMR) AF: 0.00 AC: 0 AN: 10984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15976

East Asian (EAS) AF: 0.000360 AC: 10 AN: 27770

South Asian (SAS) AF: 0.00 AC: 0 AN: 36520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41640

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

European-Non Finnish (NFE) AF: 0.0000197 AC: 19 AN: 963840

Other (OTH) AF: 0.00 AC: 0 AN: 47696

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Combined oxidative phosphorylation defect type 23 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.1
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.024	D
Polyphen		0.84	P
Vest4		0.36
MutPred		0.35		Loss of disorder (P = 0.0112)
MVP		0.52
MPC		0.88
ClinPred		0.93	D
GERP RS		4.8
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.16
gMVP		0.59
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057518138; hg19: chr19-17448428;