rs794726691
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_017775.4(TTC19):c.601_604del(p.Gly201MetfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TTC19
NM_017775.4 frameshift
NM_017775.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.86
Genes affected
TTC19 (HGNC:26006): (tetratricopeptide repeat domain 19) This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 aa each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2012]
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ACMG classification
Classification made for transcript
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 17-16006489-TGCTG-T is Pathogenic according to our data. Variant chr17-16006489-TGCTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 102437.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTC19 | NM_017775.4 | c.601_604del | p.Gly201MetfsTer8 | frameshift_variant | 7/10 | ENST00000261647.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTC19 | ENST00000261647.10 | c.601_604del | p.Gly201MetfsTer8 | frameshift_variant | 7/10 | 1 | NM_017775.4 | P1 | |
TTC19 | ENST00000497842.6 | n.711_714del | non_coding_transcript_exon_variant | 6/10 | 5 | ||||
TTC19 | ENST00000475723.5 | c.*285_*288del | 3_prime_UTR_variant, NMD_transcript_variant | 7/10 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251456Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3AN: 1460142Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 726516
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mitochondrial complex III deficiency nuclear type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2017 | The c.601_604delGGCT variant in the TTC19 gene has been reported previously in the homozygous and heterozygous states with a second TTC19 variant in association with mitochondrial complex III deficiency; note that c.601_604delGGCT has been reported using alternate nomenclature c.963_966delTGGC and c.964_967delGGCT (Nogueira et al., 2013; Atwal, 2014). The c.601_604delGGCT variant causes a frameshift starting with codon Glycine 201, changes this amino acid to a Methionine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Gly201MetfsX8. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.601_604delGGCT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.601_604delGGCT as a pathogenic variant. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at