3-158652154-C-G

Variant names:

• chr3-158652154-C-G
• rs139430866
• NM_024996.7:c.748C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_024996.7(GFM1):​c.748C>G​(p.Arg250Gly) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFM1 NM_024996.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• Publications: 11 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-158652155-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 870603.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024996.7. 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
	GFM1	NM_024996.7	MANE Select	c.748C>G	p.Arg250Gly	missense	Exon 6 of 18	NP_079272.4
	GFM1	NM_001308164.2		c.805C>G	p.Arg269Gly	missense	Exon 7 of 19	NP_001295093.1	Q96RP9-2
	GFM1	NM_001374355.1		c.805C>G	p.Arg269Gly	missense	Exon 7 of 18	NP_001361284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM1	ENST00000486715.6	TSL:1 MANE Select	c.748C>G	p.Arg250Gly	missense	Exon 6 of 18	ENSP00000419038.1	Q96RP9-1
	GFM1	ENST00000867690.1		c.826C>G	p.Arg276Gly	missense	Exon 7 of 19	ENSP00000537749.1
	GFM1	ENST00000867689.1		c.820C>G	p.Arg274Gly	missense	Exon 7 of 19	ENSP00000537748.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.86		Gain of sheet (P = 0.0477)
MVP		0.86
MPC		0.94
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.93
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs139430866; hg19: chr3-158369943;