rs587776513

Variant names:

• chr17-63606395-G-GC
• rs587776513
• NM_016360.4:c.472dupC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016360.4(TACO1):​c.472dupC​(p.His158ProfsTer8) 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: 32)
• Consequence: TACO1 NM_016360.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.03

Genes affected

TACO1 (HGNC:24316): (translational activator of cytochrome c oxidase I) This gene encodes a mitochondrial protein that function as a translational activator of mitochondrially-encoded cytochrome c oxidase 1. Mutations in this gene are associated with Leigh syndrome.[provided by RefSeq, Mar 2010]

ENSG00000288894 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 17-63606395-G-GC is Pathogenic according to our data. Variant chr17-63606395-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TACO1	NM_016360.4	c.472dupC	p.His158ProfsTer8	frameshift_variant	Exon 3 of 5	ENST00000258975.7	NP_057444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TACO1	ENST00000258975.7	c.472dupC	p.His158ProfsTer8	frameshift_variant	Exon 3 of 5	1	NM_016360.4	ENSP00000258975.6
ENSG00000288894	ENST00000690765.1	n.*298dupC		non_coding_transcript_exon_variant	Exon 10 of 12			ENSP00000510085.1
ENSG00000288894	ENST00000690765.1	n.*298dupC		3_prime_UTR_variant	Exon 10 of 12			ENSP00000510085.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.His158ProfsTer8 variant in TACO1 was identified by our study in one individual with Mitochondrial Complex IV Deficiency. This variant was absent from large population studies. The homozygous p.His158ProfsTer8 variant in TACO1 has been reported in 5 Turkish individuals with Mitochondrial Complex IV Deficiency, and segregated with disease in 5 affected relatives from one cosanguineous family. Seven additional relatives, 1 without the variant and 6 with the variant in the heterozygous state, were unaffected (PMID: 19503089). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 158 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. However, loss of function of the TACO1 gene is not an established disease mechanism in autosomal recessive Mitochrondrial Complex IV Deficiency based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In vitro functional studies with fibroblast mitochondria from a patient homozygous for this variant provide some evidence that the p.His158ProfsTer8 variant may impact protein function since Mitochondrial Complex IV levels were rescued by wild-type TACO1 expression (PMID: 19503089). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PP1 (Richards 2015). -

Mitochondrial complex 4 deficiency, nuclear type 8 Pathogenic:1

Nov 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776513; hg19: chr17-61683755;