11-68049664-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006019.4(TCIRG1):βc.1891delβ(p.Val631TrpfsTer56) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,600,344 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. E630E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006019.4 frameshift, splice_region
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCIRG1 | NM_006019.4 | c.1891del | p.Val631TrpfsTer56 | frameshift_variant, splice_region_variant | 16/20 | ENST00000265686.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCIRG1 | ENST00000265686.8 | c.1891del | p.Val631TrpfsTer56 | frameshift_variant, splice_region_variant | 16/20 | 1 | NM_006019.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000867 AC: 2AN: 230766Hom.: 0 AF XY: 0.00000788 AC XY: 1AN XY: 126826
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1448184Hom.: 0 Cov.: 33 AF XY: 0.00000971 AC XY: 7AN XY: 720638
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Autosomal recessive osteopetrosis 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 29, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 22, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 29, 2021 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 18, 2024 | Reported in published literature an individual with severe osteopetrosis; however, additional information including zygosity or familial studies were not reported (PMID: 22231430); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11532986, 10888887, 10942435, 19448635, 34203247, 22231430) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Val631Trpfs*56) 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 present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with osteopetrosis (PMID: 22231430). This variant is also known as c.1878delG (p.Val630Trpfsx56). ClinVar contains an entry for this variant (Variation ID: 555837). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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