NM_003321.5:c.162delC

Variant names:

• chr16-28845996-CG-C
• rs1057518743
• NM_003321.5:c.162delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003321.5(TUFM):​c.162delC​(p.Tyr54fs) 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUFM NM_003321.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.954
• Publications: 2 publications found

Genes affected

TUFM (HGNC:12420): (Tu translation elongation factor, mitochondrial) This gene encodes a protein which participates in protein translation in mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency resulting in lactic acidosis and fatal encephalopathy. A pseudogene has been identified on chromosome 17. [provided by RefSeq, Jul 2008]

TUFM Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 16-28845996-CG-C is Pathogenic according to our data. Variant chr16-28845996-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 372183.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003321.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	NM_003321.5	MANE Select	c.162delC	p.Tyr54fs	frameshift	Exon 2 of 10	NP_003312.3
	TUFM	NM_001365360.2		c.162delC	p.Tyr54fs	frameshift	Exon 2 of 10	NP_001352289.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	ENST00000313511.8	TSL:1 MANE Select	c.162delC	p.Tyr54fs	frameshift	Exon 2 of 10	ENSP00000322439.3
	TUFM	ENST00000565012.1	TSL:5	n.162delC		non_coding_transcript_exon	Exon 2 of 7	ENSP00000455007.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Combined oxidative phosphorylation defect type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95
Mutation Taster		=4/196	disease causing (ClinVar)

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

dbSNP: rs1057518743; hg19: chr16-28857317;