19-35907730-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_003332.4(TYROBP):c.94G>A(p.Asp32Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000254 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32E) has been classified as Likely benign.
Frequency
Consequence
NM_003332.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151968Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250690Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135678
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461864Hom.: 0 Cov.: 37 AF XY: 0.0000303 AC XY: 22AN XY: 727234
GnomAD4 genome AF: 0.0000197 AC: 3AN: 151968Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74222
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear; In silico analysis indicates that this missense variant does not alter protein structure/function; Reported in a patient with dementia; however, additional clinical information was not provided (PMID: 29930232); This variant is associated with the following publications: (PMID: 30316000, 29930232) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 32 of the TYROBP protein (p.Asp32Asn). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs758290972, gnomAD 0.02%). This missense change has been observed in individual(s) with unspecified dementia (PMID: 29930232). ClinVar contains an entry for this variant (Variation ID: 374122). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. - |
Bradykinesia;C0233794:Memory impairment;C0234376:Action tremor;C0242422:Parkinsonian disorder;C0497327:Dementia;C0740279:Cerebellar atrophy;C1858116:Caudate atrophy;C4021584:Frontotemporal cerebral atrophy;C4551583:Cerebral cortical atrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 12, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at