dbSNP rs746538436: GFM2:p.Glu213ArgfsTer3 (chr5-74746137-CT-C) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

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

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 0.334

Publications

3 publications found

Variant links:

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

GFM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFM2	NM_032380.5 link	c.636delA	p.Glu213ArgfsTer3	frameshift_variant	Exon 9 of 21	ENST00000296805.8	NP_115756.2	Q969S9-1A0A024RAK1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFM2	ENST00000296805.8 link	c.636delA	p.Glu213ArgfsTer3	frameshift_variant	Exon 9 of 21	1	NM_032380.5	ENSP00000296805.3		Q969S9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1392692

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30298

American (AMR)

AF:

0.00

AC:

AN:

28884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23122

East Asian (EAS)

AF:

0.00

AC:

AN:

38546

South Asian (SAS)

AF:

0.00

AC:

AN:

72290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5306

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1085280

Other (OTH)

AF:

0.00

AC:

AN:

57156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Mitochondrial disease

Pathogenic:1

Sep 15, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Combined oxidative phosphorylation deficiency 39

Pathogenic:1

Apr 19, 2019

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.33

Mutation Taster

=6/194

disease causing (ClinVar)

(source)

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over