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

Genomes: not found (cov: 30)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DYRK1A
NM_001347721.2 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.19
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 21-37490201-C-T is Pathogenic according to our data. Variant chr21-37490201-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 423502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-37490201-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYRK1ANM_001347721.2 linkuse as main transcriptc.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
DYRK1AENST00000647188.2 linkuse as main transcriptc.664C>T p.Arg222Ter stop_gained 7/12 NM_001347721.2 ENSP00000494572 P1Q13627-2

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250686
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135490
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460850
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726650
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingNeuberg 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 07, 2023This 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 06, 2018The 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 submitterclinical testingGeneDxAug 15, 2022Nonsense 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 submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalOct 19, 2016- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 08, 2015- -
Complex neurodevelopmental disorder Pathogenic:1
Pathogenic, no assertion criteria providedprovider interpretationGenomeConnect - Simons SearchlightNov 18, 2016Submission 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
53
DANN
Uncertain
1.0
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.91
D
MutationTaster
Benign
1.0
A;A;A;A;A;A;A
Vest4
0.87, 0.95, 0.97
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.22
Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780441716; hg19: chr21-38862503; COSMIC: COSV58295398; COSMIC: COSV58295398; API