rs191462023
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 5P and 9B. PM1PM2PP3BP4_StrongBP6BS1
The NM_024996.7(GFM1):c.622G>A(p.Glu208Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000791 in 1,580,836 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )
Consequence
GFM1
NM_024996.7 missense
NM_024996.7 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 9.23
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]
LXN (HGNC:13347): (latexin) This gene encodes the only known protein inhibitor of zinc-dependent metallocarboxypeptidases. The encoded protein, latexin, downregulates the population size of hematopoietic stem cells. This protein is found to be downregulated in cancer cells because of promoter hypermethylation. [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM1
In a domain tr-type G (size 277) in uniprot entity EFGM_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_024996.7
PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.057215482).
BP6
Variant 3-158649090-G-A is Benign according to our data. Variant chr3-158649090-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214492.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000138 (21/152284) while in subpopulation EAS AF= 0.00386 (20/5188). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000346 AC: 87AN: 251390Hom.: 0 AF XY: 0.000309 AC XY: 42AN XY: 135876
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GnomAD4 exome AF: 0.0000728 AC: 104AN: 1428552Hom.: 0 Cov.: 25 AF XY: 0.0000828 AC XY: 59AN XY: 712890
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74470
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 23, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2017 | The E208K missense change has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. E208K has been reported in 1000 Genomes at a frequency of 1% in the Chinese Han population in Bejing and at a frequency of 0.5% in the Southern Chinese Han population. E208K is a non-conservative amino acid substitution as a negatively charged Glutamic acid residue is replaced with a positively charged Lysine residue at a position that is highly conserved across species. Multiple in silico algorithyms predict that E208K is damaging to the GFM1 protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at