rs1554996130
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006019.4(TCIRG1):c.922del(p.Gln308SerfsTer4) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
TCIRG1
NM_006019.4 frameshift
NM_006019.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.801
Genes affected
TCIRG1 (HGNC:11647): (T cell immune regulator 1, ATPase H+ transporting V0 subunit a3) This gene encodes a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). The protein complex acts as a pump to move protons across the membrane. This movement of protons helps regulate the pH of cells and their surrounding environment. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is comprised of a cytosolic V1 domain and a transmembrane V0 domain. Alternative splicing results in multiple transcript variants. Mutations in this gene are associated with infantile malignant osteopetrosis. [provided by RefSeq, May 2017]
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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 11-68044244-AC-A is Pathogenic according to our data. Variant chr11-68044244-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 5459.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCIRG1 | NM_006019.4 | c.922del | p.Gln308SerfsTer4 | frameshift_variant | 9/20 | ENST00000265686.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCIRG1 | ENST00000265686.8 | c.922del | p.Gln308SerfsTer4 | frameshift_variant | 9/20 | 1 | NM_006019.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive osteopetrosis 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2000 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change creates a premature translational stop signal (p.Gln308Serfs*4) in the TCIRG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCIRG1 are known to be pathogenic (PMID: 10888887, 10942435, 11532986, 19448635). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with osteopetrosis (PMID: 10888887). This variant is also known as delC5272. ClinVar contains an entry for this variant (Variation ID: 5459). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at