8-144429153-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_013432.5(TONSL):c.4127G>A(p.Arg1376Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000654 in 1,529,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_013432.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TONSL | NM_013432.5 | c.4127G>A | p.Arg1376Gln | missense_variant | 26/26 | ENST00000409379.8 | NP_038460.4 | |
TONSL | XM_011517048.3 | c.3155G>A | p.Arg1052Gln | missense_variant | 19/19 | XP_011515350.1 | ||
TONSL | XM_011517049.3 | c.3119G>A | p.Arg1040Gln | missense_variant | 19/19 | XP_011515351.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TONSL | ENST00000409379.8 | c.4127G>A | p.Arg1376Gln | missense_variant | 26/26 | 1 | NM_013432.5 | ENSP00000386239.3 | ||
TONSL | ENST00000497613.2 | n.6229G>A | non_coding_transcript_exon_variant | 17/17 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000752 AC: 1AN: 133044Hom.: 0 AF XY: 0.0000139 AC XY: 1AN XY: 71838
GnomAD4 exome AF: 0.00000363 AC: 5AN: 1377476Hom.: 0 Cov.: 30 AF XY: 0.00000441 AC XY: 3AN XY: 679592
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 19, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1376 of the TONSL protein (p.Arg1376Gln). 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 variant has not been reported in the literature in individuals affected with TONSL-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at