rs724159949

chr21-37486563-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001347721.2(DYRK1A):c.586C>T(p.Arg196Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000693 in 1,443,298 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DYRK1A NM_001347721.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 6.17

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]

LOC105372797 (HGNC:):

ACMG classification

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 21-37486563-C-T is Pathogenic according to our data. Variant chr21-37486563-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 162153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-37486563-C-T is described in Lovd as [Pathogenic]. Variant chr21-37486563-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2	c.586C>T	p.Arg196Ter	stop_gained	6/12	ENST00000647188.2
LOC105372797	XR_001755034.2	n.138+2989G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2	c.586C>T	p.Arg196Ter	stop_gained	6/12		NM_001347721.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443298 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory de novo in a 5-year-old male with global delays, autism, microcephaly, dysmorphic features, ptosis -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162153 / PMID: 25167861). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 09, 2022	This sequence change creates a premature translational stop signal (p.Arg205*) 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 DYRK1A-related disease (PMID: 25167861, 25641759, 25920557, 25944381; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162153). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Sep 15, 2014	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous p.Arg205Ter variant in DYRK1A was identified by our study in one individual with intellectual disability, feeding difficulties, and dysmorphic facial features. The p.Arg205Ter variant in DYRK1A has been previously reported in the literature in 10 unrelated individuals with DYRK1A-related intellectual disability syndrome (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 32581362, PMID: 25920557). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 9 individuals with confirmed paternity and maternity (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 25920557, SCV002521469.1, SCV000196058.1). This variant has also been reported in ClinVar (Variation ID: 162153) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg205Ter variant may impact protein function (PMID 28167836, PMID: 31263215). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 205, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DYRK1A gene is an established disease mechanism in autosomal dominant DYRK1A-related intellectual disability syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DYRK1A-related intellectual disability syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS3_Moderate, PS4, PM2_Supporting (Richards 2015). -

Feeding difficulties;C0423224:Deeply set eye;C3276611:Absent or delayed speech development;C3714756:Intellectual disability;C4551563:Microcephaly Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Sep 09, 2014

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Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2020

The alteration results in a premature stop codon:_x000D_ _x000D_ The c.613C>T (p.R205*) alteration, located in coding exon 5 of the DYRK1A gene, results from a C to T substitution at nucleotide position 613. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 205. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the DYRK1A NM_001396 c.613C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported to have occurred de novo in multiple individuals with features consistent with a DYRK1A-related neurodevelopmental disorder including intellectual disability/developmental delay, seizures, microcephaly and dysmorphic facial features (Redin, 2014; Ruaud, 2015; Ji, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2023

Published functional studies demonstrate a loss of function effect (Dang et al., 2017; Blackburn et al., 2019); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34345024, 25641759, 26922654, 25944381, 25920557, 31263215, 32581362, 25167861, 28167836, 32838606, 33562844, 35873028, 35285131) -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Jul 25, 2014

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Microphthalmia;C0234533:Generalized-onset seizure;C0557874:Global developmental delay;C4551563:Microcephaly Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.76, 0.93, 0.91
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs724159949; hg19: chr21-38858865; COSMIC: COSV58294256; COSMIC: COSV58294256;