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rs794726691

Positions:

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.86
Variant links:
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
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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
TTC19NM_017775.4 linkuse as main transcriptc.601_604del p.Gly201MetfsTer8 frameshift_variant 7/10 ENST00000261647.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTC19ENST00000261647.10 linkuse as main transcriptc.601_604del p.Gly201MetfsTer8 frameshift_variant 7/101 NM_017775.4 P1
TTC19ENST00000497842.6 linkuse as main transcriptn.711_714del non_coding_transcript_exon_variant 6/105
TTC19ENST00000475723.5 linkuse as main transcriptc.*285_*288del 3_prime_UTR_variant, NMD_transcript_variant 7/102

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251456
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000205
AC:
3
AN:
1460142
Hom.:
0
AF XY:
0.00000275
AC XY:
2
AN XY:
726516
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000756

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 providedliterature onlyOMIMMay 01, 2013- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 02, 2017The 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs794726691; hg19: chr17-15909803; API