Genetic Variant NM_032620.4:c.1291delC (chr19-17341512-AC-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_032620.4(GTPBP3):c.1291delC(p.Arg431GlufsTer38) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,460,844 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GTPBP3
NM_032620.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.32

Publications

0 publications found

Variant links:

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

GTPBP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.127 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTPBP3	NM_032620.4 link	c.1291delC	p.Arg431GlufsTer38	frameshift_variant	Exon 9 of 9	ENST00000324894.13	NP_116009.2	Q969Y2-1
GTPBP3	NM_133644.4 link	c.1387delC	p.Arg463GlufsTer38	frameshift_variant	Exon 8 of 8		NP_598399.2	Q969Y2-2B7Z563
GTPBP3	NM_001195422.1 link	c.1357delC	p.Arg453GlufsTer38	frameshift_variant	Exon 9 of 9		NP_001182351.1	Q969Y2-4B7Z563
GTPBP3	NM_001128855.3 link	c.1228delC	p.Arg410GlufsTer38	frameshift_variant	Exon 9 of 9		NP_001122327.1	Q969Y2-3B7Z563

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GTPBP3	ENST00000324894.13 link	c.1291delC	p.Arg431GlufsTer38	frameshift_variant	Exon 9 of 9	1	NM_032620.4	ENSP00000313818.7		Q969Y2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460844

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111546

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over