rs1057518742

Variant names:

• chr16-28845030-A-T
• rs1057518742
• NM_003321.5:c.440T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003321.5(TUFM):​c.440T>A​(p.Leu147His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUFM NM_003321.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.71
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 16-28845030-A-T is Pathogenic according to our data. Variant chr16-28845030-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 372182.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	NM_003321.5	MANE Select	c.440T>A	p.Leu147His	missense	Exon 4 of 10	NP_003312.3
	TUFM	NM_001365360.2		c.440T>A	p.Leu147His	missense	Exon 4 of 10	NP_001352289.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	ENST00000313511.8	TSL:1 MANE Select	c.440T>A	p.Leu147His	missense	Exon 4 of 10	ENSP00000322439.3
	TUFM	ENST00000916490.1		c.440T>A	p.Leu147His	missense	Exon 4 of 11	ENSP00000586549.1
	TUFM	ENST00000916489.1		c.440T>A	p.Leu147His	missense	Exon 4 of 10	ENSP00000586548.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

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
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	0.98
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.0094	D
PhyloP100		8.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.88
MVP		0.72
MPC		1.8
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
gMVP		0.83
Mutation Taster		=41/59	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: rs1057518742; hg19: chr16-28856351;