rs780441716
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001347721.2(DYRK1A):c.664C>T(p.Arg222Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,850 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001347721.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYRK1A | NM_001347721.2 | c.664C>T | p.Arg222Ter | stop_gained | 7/12 | ENST00000647188.2 | NP_001334650.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYRK1A | ENST00000647188.2 | c.664C>T | p.Arg222Ter | stop_gained | 7/12 | NM_001347721.2 | ENSP00000494572 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250686Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135490
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460850Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726650
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
DYRK1A-related intellectual disability syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop-gained variant c.664C>T (p.Arg222Ter) in DYRK1A has been reported previously as a de novo variant in an individual (Fitzgerald et al., 2015). This variant has been reported to the ClinVar database as Pathogenic. The c.664C>T variant is reported with allele frequency 0.0004% in gnomAD exomes and novel in 1000 Genomes. The nucleotide change c.664C>T in DYRK1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic . - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 07, 2023 | This sequence change creates a premature translational stop signal (p.Arg231*) in the DYRK1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYRK1A are known to be pathogenic (PMID: 25944381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a neurodevelopmental disorder and multiple congenital anomalies (PMID: 28053047). ClinVar contains an entry for this variant (Variation ID: 423502). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 06, 2018 | The DYRK1A c.691C>T (p.Arg231Ter) stop gained variant has been reported in a de novo heterozygous state in two individuals with the key features of DYRK1A-related intellectual disability syndrome, including intellectual disability, developmental delay, microcephaly, and characteristic dysmorphic facial features (Fitzgerald et al. 2015; Valencia et al. 2015; Evers et al. 2017). At least one of the two also showed cardiac defect, ophthalmological abnormality, poor weight gain, delayed speech development, and short stature. The p.Arg231Ter variant is not present in the Genome Aggregation Database. Functional studies of the variant have not been conducted, but it is predicted to produce an absent or severely truncated protein product, including loss of more than half of the protein kinase domain. Based on the collective evidence, the c.691C>T p.Arg231Ter variant is classified as pathogenic for DYRK1A-related intellectual disability syndrome. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25533962, 28053047, 28135719, 30564305, 33562844, 31785789, 33004838) - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 19, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 08, 2015 | - - |
Complex neurodevelopmental disorder Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Nov 18, 2016 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-11-18 and interpreted as Pathogenic. Variant was initially reported on 2016-10-20 by GTR ID of laboratory name 1238. The reporting laboratory might also submit to ClinVar. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at