chr16-28845029-GA-AT

Variant names:

• chr16-28845029-GA-AT
• NM_003321.5:c.440_441delTCinsAT
• TUFM p.Leu147His

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_003321.5(TUFM):​c.440_441delTCinsAT​(p.Leu147His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUFM NM_003321.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.71
• Publications: 0 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_003321.5 (TUFM) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	NM_003321.5	MANE Select	c.440_441delTCinsAT	p.Leu147His	missense	N/A	NP_003312.3
	TUFM	NM_001365360.2		c.440_441delTCinsAT	p.Leu147His	missense	N/A	NP_001352289.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	ENST00000313511.8	TSL:1 MANE Select	c.440_441delTCinsAT	p.Leu147His	missense	N/A	ENSP00000322439.3	P49411
	TUFM	ENST00000916490.1		c.440_441delTCinsAT	p.Leu147His	missense	N/A	ENSP00000586549.1
	TUFM	ENST00000916489.1		c.440_441delTCinsAT	p.Leu147His	missense	N/A	ENSP00000586548.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-28856350;