rs140963213
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2
The NM_006019.4(TCIRG1):c.1249G>A(p.Ala417Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00378 in 1,613,942 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006019.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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TCIRG1 | NM_006019.4 | c.1249G>A | p.Ala417Thr | missense_variant | Exon 11 of 20 | ENST00000265686.8 | NP_006010.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00264 AC: 402AN: 152064Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00254 AC: 637AN: 250824Hom.: 2 AF XY: 0.00258 AC XY: 351AN XY: 135786
GnomAD4 exome AF: 0.00390 AC: 5705AN: 1461760Hom.: 12 Cov.: 36 AF XY: 0.00381 AC XY: 2774AN XY: 727190
GnomAD4 genome AF: 0.00264 AC: 401AN: 152182Hom.: 2 Cov.: 33 AF XY: 0.00220 AC XY: 164AN XY: 74390
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:2
TCIRG1: BS2 -
Reported with another TCIRG1 variant in two families with osteopetrosis in published literature (Afshariyamchlou et al., 2022; Jaber et al., 2022); Reported in an additional patient in published literature with severe osteopetrosis; however, further information such as zygosity or presence of another variant was not provided (Pangrazio et al., 2012); Reported in published literature in association with other phenotypes, including lower absolute neutrophil count and risk for glioma, but additional research is needed to explore a possible link between TCIRG1 variants and these phenotypes (Rosenthal et al., 2016; Kinnersley et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34426522, 33206719, 26264438, 27229898, 35573728, 35802155, 35720663, 22231430) -
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The TCIRG1 p.Ala201Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs140963213) and in ClinVar (classified as a VUS by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics and Fulgent Genetics for Osteopetrosis autosomal recessive 1). The variant was identified in control databases in 727 of 282162 chromosomes (2 homozygous) at a frequency of 0.002577 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 548 of 128706 chromosomes (freq: 0.004258), Ashkenazi Jewish in 26 of 10332 chromosomes (freq: 0.002516), Latino in 84 of 35396 chromosomes (freq: 0.002373), Other in 15 of 7212 chromosomes (freq: 0.00208), European (Finnish) in 25 of 25086 chromosomes (freq: 0.000997), African in 22 of 24876 chromosomes (freq: 0.000884), South Asian in 6 of 30616 chromosomes (freq: 0.000196) and East Asian in 1 of 19938 chromosomes (freq: 0.00005). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ala201 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Autosomal recessive osteopetrosis 1 Uncertain:3Benign:1Other:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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The TCIRG1 c.1249G>A (p.Ala417Thr) missense change has a maximum subpopulation frequency of 0.43% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with autosomal recessive osteopetrosis (PMID: 22231430, 35720663, 35802155). This variant has also been associated with high-risk glioma (PMID: 26264438) and lower neutrophil count (PMID: 27229898). To our knowledge, this variant has not been reported in individuals with severe congenital neutropenia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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Increased bone mineral density Uncertain:1
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TCIRG1-related disorder Uncertain:1
The TCIRG1 c.1249G>A variant is predicted to result in the amino acid substitution p.Ala417Thr. This variant was reported in a cohort of patients with osteopetrosis; however, no additional clinical or functional information was provided to assess the pathogenicity of this variant (Pangrazio et al. 2012. PubMed ID: 22231430). In addition, this variant has been reported the compound heterozygous state with the TCIRG1 c.1735G>A (p.Gly579Arg) variant in at least three patients with osteopetrosis (Jaber et al. 2022. PubMed ID: 35802155; siblings reported in Afshariyamchlou et al. 2022. PubMed ID: 35720663).This variant is reported in 0.43% of alleles in individuals of European (Non-Finnish) descent in gnomAD including 2 homozygous inviduals which is more frequent than expected for disease-causing variants in this gene. This variant has conflicting intepretations in ClinVar ranging from uncertain to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/235702). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Neutropenia, severe congenital, 1, autosomal dominant Uncertain:1
The TCIRG1 c.1249G>A (p.Ala417Thr) missense change has a maximum subpopulation frequency of 0.43% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with autosomal recessive osteopetrosis (PMID: 22231430, 35720663, 35802155). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at