11-68044303-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006019.4(TCIRG1):c.979C>T(p.Arg327*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,602,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R327R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006019.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TCIRG1 | NM_006019.4 | c.979C>T | p.Arg327* | stop_gained | Exon 9 of 20 | ENST00000265686.8 | NP_006010.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000401 AC: 9AN: 224624Hom.: 0 AF XY: 0.0000244 AC XY: 3AN XY: 122720
GnomAD4 exome AF: 0.0000207 AC: 30AN: 1450312Hom.: 0 Cov.: 33 AF XY: 0.0000167 AC XY: 12AN XY: 720648
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Autosomal recessive osteopetrosis 1 Pathogenic:3
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg327*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with osteopetrosis (PMID: 22231430). ClinVar contains an entry for this variant (Variation ID: 550832). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at