3-158646232-C-CT

Variant names:

• chr3-158646232-C-CT
• NM_024996.7:c.303dupT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024996.7(GFM1):​c.303dupT​(p.Ile102TyrfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFM1 NM_024996.7 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.38
• Publications: 0 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: Pathogenic. The variant received 18 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 3-158646232-C-CT is Pathogenic according to our data. Variant chr3-158646232-C-CT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2077405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.303dupT	p.Ile102TyrfsTer16	frameshift	Exon 3 of 18	NP_079272.4
	GFM1	NM_001308164.2		c.303dupT	p.Ile102TyrfsTer16	frameshift	Exon 3 of 19	NP_001295093.1	Q96RP9-2
	GFM1	NM_001374355.1		c.303dupT	p.Ile102TyrfsTer16	frameshift	Exon 3 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.303dupT	p.Ile102TyrfsTer16	frameshift	Exon 3 of 18	ENSP00000419038.1	Q96RP9-1
	GFM1	ENST00000867690.1		c.303dupT	p.Ile102TyrfsTer16	frameshift	Exon 3 of 19	ENSP00000537749.1
	GFM1	ENST00000867689.1		c.303dupT	p.Ile102TyrfsTer16	frameshift	Exon 3 of 19	ENSP00000537748.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4

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

Other links and lift over

hg19: chr3-158364021;