chr19-17337656-G-A

Variant names:

• chr19-17337656-G-A
• rs1371040711
• NM_032620.4:c.45G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_032620.4(GTPBP3):​c.45G>A​(p.Gly15Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GTPBP3 NM_032620.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.69
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 19-17337656-G-A is Benign according to our data. Variant chr19-17337656-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2877810.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.69 with no splicing effect.

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.45G>A	p.Gly15Gly	synonymous	Exon 1 of 9	NP_116009.2	Q969Y2-1
	GTPBP3	NM_133644.4		c.45G>A	p.Gly15Gly	synonymous	Exon 1 of 8	NP_598399.2	Q969Y2-2
	GTPBP3	NM_001128855.3		c.45G>A	p.Gly15Gly	synonymous	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.45G>A	p.Gly15Gly	synonymous	Exon 1 of 9	ENSP00000313818.7	Q969Y2-1
	GTPBP3	ENST00000600625.5	TSL:1	c.45G>A	p.Gly15Gly	synonymous	Exon 1 of 9	ENSP00000473150.1	Q969Y2-3
	GTPBP3	ENST00000600610.5	TSL:1	n.45G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000469008.1	M0QXA1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1183534 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 565890

African (AFR) AF: 0.00 AC: 0 AN: 23522

American (AMR) AF: 0.00 AC: 0 AN: 11000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16194

East Asian (EAS) AF: 0.00 AC: 0 AN: 27928

South Asian (SAS) AF: 0.00 AC: 0 AN: 39224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4800

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 970524

Other (OTH) AF: 0.00 AC: 0 AN: 48210

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152302 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

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

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	GTPBP3-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		1.7
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1371040711; hg19: chr19-17448465;