rs797044523
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001347721.2(DYRK1A):c.425dupA(p.Asn142LysfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N142N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
DYRK1A
NM_001347721.2 frameshift
NM_001347721.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0540
Publications
6 publications found
Genes affected
DYRK1A (HGNC:3091): (dual specificity tyrosine phosphorylation regulated kinase 1A) This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. This gene is a homolog of Drosophila mnb (minibrain) gene and rat Dyrk gene. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Alternative splicing of this gene generates several transcript variants differing from each other either in the 5' UTR or in the 3' coding region. These variants encode at least five different isoforms. [provided by RefSeq, Jul 2008]
DYRK1A Gene-Disease associations (from GenCC):
- complex neurodevelopmental disorderInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- DYRK1A-related intellectual disability syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 21-37480756-T-TA is Pathogenic according to our data. Variant chr21-37480756-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 204008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DYRK1A | NM_001347721.2 | c.425dupA | p.Asn142LysfsTer12 | frameshift_variant | Exon 5 of 12 | ENST00000647188.2 | NP_001334650.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DYRK1A | ENST00000647188.2 | c.425dupA | p.Asn142LysfsTer12 | frameshift_variant | Exon 5 of 12 | NM_001347721.2 | ENSP00000494572.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460466Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726534 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1460466
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
726534
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33422
American (AMR)
AF:
AC:
0
AN:
44474
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26098
East Asian (EAS)
AF:
AC:
0
AN:
39594
South Asian (SAS)
AF:
AC:
0
AN:
85930
European-Finnish (FIN)
AF:
AC:
0
AN:
53392
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111450
Other (OTH)
AF:
AC:
0
AN:
60344
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
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1
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2
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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4
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<30
30-35
35-40
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
DYRK1A-related intellectual disability syndrome Pathogenic:2
Sep 15, 2014
UCLA Clinical Genomics Center, UCLA
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Jan 01, 2025
Center of Human Genetics, Hôpital Erasme
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Inborn genetic diseases Pathogenic:1
Nov 03, 2016
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
not provided Pathogenic:1
-
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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