rs746538436

Variant names:

• chr5-74746137-CT-C
• rs746538436
• NM_032380.5:c.636delA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032380.5(GFM2):​c.636delA​(p.Glu213ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,392,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GFM2 NM_032380.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.334
• Publications: 3 publications found

Genes affected

GFM2 (HGNC:29682): (GTP dependent ribosome recycling factor mitochondrial 2) Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors, which is a GTPase that plays a role at the termination of mitochondrial translation by mediating the disassembly of ribosomes from messenger RNA . Its role in the regulation of normal mitochondrial function and in disease states attributed to mitochondrial dysfunction is not known. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2013]

GFM2 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 39

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-74746137-CT-C is Pathogenic according to our data. Variant chr5-74746137-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 440787.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032380.5. 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
	GFM2	NM_032380.5	MANE Select	c.636delA	p.Glu213ArgfsTer3	frameshift	Exon 9 of 21	NP_115756.2
	GFM2	NM_001281302.2		c.732delA	p.Glu245ArgfsTer3	frameshift	Exon 10 of 22	NP_001268231.1
	GFM2	NM_170691.3		c.636delA	p.Glu213ArgfsTer3	frameshift	Exon 9 of 20	NP_733792.1	Q969S9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM2	ENST00000296805.8	TSL:1 MANE Select	c.636delA	p.Glu213ArgfsTer3	frameshift	Exon 9 of 21	ENSP00000296805.3	Q969S9-1
	GFM2	ENST00000509430.5	TSL:1	c.636delA	p.Glu213ArgfsTer3	frameshift	Exon 10 of 22	ENSP00000427004.1	Q969S9-1
	GFM2	ENST00000345239.6	TSL:1	c.636delA	p.Glu213ArgfsTer3	frameshift	Exon 9 of 20	ENSP00000296804.3	Q969S9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1392692 Hom.: 0 Cov.: 26 AF XY: 0.00000145 AC XY: 1 AN XY: 690270

African (AFR) AF: 0.00 AC: 0 AN: 30298

American (AMR) AF: 0.00 AC: 0 AN: 28884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23122

East Asian (EAS) AF: 0.00 AC: 0 AN: 38546

South Asian (SAS) AF: 0.00 AC: 0 AN: 72290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5306

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085280

Other (OTH) AF: 0.00 AC: 0 AN: 57156

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Combined oxidative phosphorylation deficiency 39 (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs746538436; hg19: chr5-74041962;