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GeneBe

3-158644650-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024996.7(GFM1):c.16G>C(p.Ala6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

GFM1
NM_024996.7 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.441
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08562189).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GFM1NM_024996.7 linkuse as main transcriptc.16G>C p.Ala6Pro missense_variant 1/18 ENST00000486715.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GFM1ENST00000486715.6 linkuse as main transcriptc.16G>C p.Ala6Pro missense_variant 1/181 NM_024996.7 P1Q96RP9-1
GFM1ENST00000264263.9 linkuse as main transcriptc.16G>C p.Ala6Pro missense_variant 1/195 Q96RP9-2
GFM1ENST00000478576.5 linkuse as main transcriptc.16G>C p.Ala6Pro missense_variant 1/142
GFM1ENST00000478254.5 linkuse as main transcriptc.16G>C p.Ala6Pro missense_variant, NMD_transcript_variant 1/185

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 15, 2014p.Ala6Pro (GCT>CCT): c.16 G>C in exon 1 of the GFM1 gene (NM_024996.5). The A6P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A6P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Benign
-0.38
Cadd
Benign
9.3
Dann
Benign
0.84
DEOGEN2
Benign
0.030
T;T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.68
T;T;T
M_CAP
Uncertain
0.087
D
MetaRNN
Benign
0.086
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
L;.;L
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.34
N;N;N
REVEL
Benign
0.072
Sift
Benign
0.077
T;T;T
Sift4G
Benign
0.12
T;T;T
Polyphen
0.38
B;B;.
Vest4
0.31
MutPred
0.46
Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);
MVP
0.061
MPC
0.29
ClinPred
0.15
T
GERP RS
-0.57
Varity_R
0.098
gMVP
0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863224031; hg19: chr3-158362439; API