Genetic Variant NM_001195422.1:c.120-522G>A (chr19-17337486-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001195422.1(GTPBP3):c.120-522G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,257,846 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 224 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 127 hom. )

Consequence

GTPBP3
NM_001195422.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.03

Publications

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

GTPBP3 links:

ENSG00000307319 (HGNC:):

ENSG00000307319 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 19-17337486-G-A is Benign according to our data. Variant chr19-17337486-G-A is described in ClinVar as Benign. ClinVar VariationId is 1270570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195422.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GTPBP3	NM_001195422.1		c.120-522G>A	intron	N/A	NP_001182351.1	B7Z563
GTPBP3	NM_032620.4	MANE Select	c.-126G>A	upstream_gene	N/A	NP_116009.2	Q969Y2-1
GTPBP3	NM_133644.4		c.-126G>A	upstream_gene	N/A	NP_598399.2	Q969Y2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GTPBP3	ENST00000361619.9	TSL:2	c.120-522G>A	intron	N/A	ENSP00000354598.4	Q969Y2-4
GTPBP3	ENST00000598038.5	TSL:5	n.763G>A	non_coding_transcript_exon	Exon 1 of 9
GTPBP3	ENST00000594345.5	TSL:3	n.466+329G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0299

AC:

4554

AN:

152152

Hom.:

224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0264

GnomAD4 exome

AF:

0.00287

AC:

3168

AN:

1105576

Hom.:

127

Cov.:

AF XY:

0.00267

AC XY:

1393

AN XY:

522536

show subpopulations

African (AFR)

AF:

0.107

AC:

2473

AN:

23040

American (AMR)

AF:

0.00914

AC:

AN:

9190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14520

East Asian (EAS)

AF:

0.000639

AC:

AN:

26604

South Asian (SAS)

AF:

0.000187

AC:

AN:

21410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35932

Middle Eastern (MID)

AF:

0.00386

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

0.000307

AC:

284

AN:

926352

Other (OTH)

AF:

0.00653

AC:

290

AN:

44378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

137

274

412

549

686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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

AF:

0.0299

AC:

4557

AN:

152270

Hom.:

224

Cov.:

AF XY:

0.0291

AC XY:

2168

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.104

AC:

4335

AN:

41538

American (AMR)

AF:

0.00981

AC:

150

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68036

Other (OTH)

AF:

0.0261

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

210

420

629

839

1049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0279

Hom.:

Bravo

AF:

0.0333

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.38

(source)

DANN

Benign

0.73

PhyloP100

-1.0

PromoterAI

-0.056

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over