3-158644637-G-A

Position:

• chr3-158644637-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024996.7(GFM1):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFM1 NM_024996.7 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.43

Genes affected

GFM1 (HGNC:13780): (G elongation factor mitochondrial 1) 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. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-158644637-G-A is Pathogenic according to our data. Variant chr3-158644637-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 214491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFM1	NM_024996.7	c.3G>A	p.Met1?	start_lost	1/18	ENST00000486715.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFM1	ENST00000486715.6	c.3G>A	p.Met1?	start_lost	1/18	1	NM_024996.7	P1
GFM1	ENST00000264263.9	c.3G>A	p.Met1?	start_lost	1/19	5
GFM1	ENST00000478576.5	c.3G>A	p.Met1?	start_lost	1/14	2
GFM1	ENST00000478254.5	c.3G>A	p.Met1?	start_lost, NMD_transcript_variant	1/18	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1417986 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 701060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2013

p.Met1? (ATG>?): c.3 G>A in exon 1 of the GFM1 gene (NM_024996.5). The c.3 G>A mutation has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The c.3 G>A mutation alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Therefore, c.3 G>A is expected to be a pathogenic mutation. The variant is found in MITONUC-MITOP panel(s)." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.15	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.082	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.73
MutPred		0.92		Loss of solvent accessibility (P = 0.008);Loss of solvent accessibility (P = 0.008);Loss of solvent accessibility (P = 0.008);
MVP		0.56
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.66
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs863224030; hg19: chr3-158362426;