19-16485252-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2
The NM_145046.5(CALR3):c.403G>A(p.Asp135Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000255 in 1,598,358 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D135G) has been classified as Uncertain significance.
Frequency
Consequence
NM_145046.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CALR3 | NM_145046.5 | c.403G>A | p.Asp135Asn | missense_variant | 4/9 | ENST00000269881.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CALR3 | ENST00000269881.8 | c.403G>A | p.Asp135Asn | missense_variant | 4/9 | 1 | NM_145046.5 | P1 | |
CALR3 | ENST00000600762.1 | c.190G>A | p.Asp64Asn | missense_variant | 3/4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 151952Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000762 AC: 19AN: 249342Hom.: 0 AF XY: 0.0000668 AC XY: 9AN XY: 134808
GnomAD4 exome AF: 0.000270 AC: 390AN: 1446406Hom.: 0 Cov.: 28 AF XY: 0.000255 AC XY: 184AN XY: 720366
GnomAD4 genome AF: 0.000112 AC: 17AN: 151952Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6AN XY: 74190
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hypertrophic cardiomyopathy 19 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 135 of the CALR3 protein (p.Asp135Asn). This variant is present in population databases (rs143932873, gnomAD 0.02%). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 25163546, 29988065, 30847666). ClinVar contains an entry for this variant (Variation ID: 410619). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CALR3 protein function with a positive predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at