rs756394857

Variant names:

• chr19-17337628-G-A
• rs756394857
• NM_032620.4:c.17G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-17337628-G-A
• chr19-17337628-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032620.4(GTPBP3):​c.17G>A​(p.Trp6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,336,862 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: GTPBP3 NM_032620.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.04
• Publications: 1 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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-17337628-G-A is Pathogenic according to our data. Variant chr19-17337628-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1405745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.17G>A	p.Trp6*	stop_gained	Exon 1 of 9	NP_116009.2	Q969Y2-1
	GTPBP3	NM_133644.4		c.17G>A	p.Trp6*	stop_gained	Exon 1 of 8	NP_598399.2	Q969Y2-2
	GTPBP3	NM_001128855.3		c.17G>A	p.Trp6*	stop_gained	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.17G>A	p.Trp6*	stop_gained	Exon 1 of 9	ENSP00000313818.7	Q969Y2-1
	GTPBP3	ENST00000600625.5	TSL:1	c.17G>A	p.Trp6*	stop_gained	Exon 1 of 9	ENSP00000473150.1	Q969Y2-3
	GTPBP3	ENST00000600610.5	TSL:1	n.17G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000469008.1	M0QXA1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000169 AC: 2 AN: 1184658 Hom.: 0 Cov.: 30 AF XY: 0.00000353 AC XY: 2 AN XY: 566342

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23560

American (AMR) AF: 0.0000891 AC: 1 AN: 11220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16272

East Asian (EAS) AF: 0.00 AC: 0 AN: 28078

South Asian (SAS) AF: 0.00 AC: 0 AN: 39002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4826

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 971272

Other (OTH) AF: 0.00 AC: 0 AN: 48244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.59	D
PhyloP100		2.0
Vest4		0.10
GERP RS		4.8
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=50/150	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs756394857; hg19: chr19-17448437;