rs143158265
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_145046.5(CALR3):c.483C>A(p.Ile161=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,596,318 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 10 hom. )
Consequence
CALR3
NM_145046.5 synonymous
NM_145046.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.74
Genes affected
CALR3 (HGNC:20407): (calreticulin 3) The protein encoded by this gene belongs to the calreticulin family, members of which are calcium-binding chaperones localized mainly in the endoplasmic reticulum. This protein is also localized to the endoplasmic reticulum lumen, however, its capacity for calcium-binding may be absent or much lower than other family members. This gene is specifically expressed in the testis, and may be required for sperm fertility. Mutation in this gene has been associated with familial hypertrophic cardiomyopathy. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
?
Variant 19-16485172-G-T is Benign according to our data. Variant chr19-16485172-G-T is described in ClinVar as [Benign]. Clinvar id is 241951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16485172-G-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=2.74 with no splicing effect.
BS2
?
High AC in GnomAd4 at 268 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CALR3 | NM_145046.5 | c.483C>A | p.Ile161= | synonymous_variant | 4/9 | ENST00000269881.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CALR3 | ENST00000269881.8 | c.483C>A | p.Ile161= | synonymous_variant | 4/9 | 1 | NM_145046.5 | P1 | |
CALR3 | ENST00000600762.1 | c.270C>A | p.Ile90= | synonymous_variant | 3/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00176 AC: 268AN: 152110Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00211 AC: 529AN: 250414Hom.: 2 AF XY: 0.00199 AC XY: 269AN XY: 135352
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GnomAD4 exome AF: 0.00105 AC: 1516AN: 1444090Hom.: 10 Cov.: 28 AF XY: 0.00107 AC XY: 769AN XY: 719598
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GnomAD4 genome ? AF: 0.00176 AC: 268AN: 152228Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 177AN XY: 74430
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hypertrophic cardiomyopathy 19 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Jun 28, 2017 | - - |
CALR3-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 08, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2017 | Variant summary: The CALR3 c.483C>A (p.Ile161Ile) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 209/112688 control chromosomes (1 homozygote) from ExAC, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.01888 (122/6462). This frequency is about 755 times the estimated maximal expected allele frequency of a pathogenic CALR3 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. One clinical diagnostic laboratory has classified this variant as benign. To our knowledge, the variant has not been reported in affected individuals in literature. Taken together, this variant is classified as benign. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at