rs797045041

Variant names:

• chr21-37505443-G-A
• rs797045041
• NM_001347721.2:c.1373G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001347721.2(DYRK1A):​c.1373G>A​(p.Arg458Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R458L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.92
• Publications: 13 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 disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• DYRK1A-related intellectual disability syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 21-37505443-G-A is Pathogenic according to our data. Variant chr21-37505443-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 209150.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.1373G>A	p.Arg458Gln	missense_variant	Exon 10 of 12	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.1373G>A	p.Arg458Gln	missense_variant	Exon 10 of 12		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Pathogenic:2

Feb 03, 2014

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in a 19-year-old female with developmental regression, intellectual disability, hypotonia, mild ataxia, intention tremor, dysmorphisms, primary microcephaly, failure to thrive, demyelination, sun sensitivity, incontinence and anxiety. -

Jun 01, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced protein stability and abrogated tyrosine autophosphorylation (Widowati et al., 2018; Courraud et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31526516, 31785789, 31263215, 30952489, 30831192, 29700199, 26633545, 25641759, 28053047, 34345024) -

Intellectual disability Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complex neurodevelopmental disorder Pathogenic:1

Nov 10, 2016

GenomeConnect - Simons Searchlight

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-11-10 and interpreted as Likely Pathogenic. Variant was initially reported on 2014-02-03 by GTR ID of laboratory name 1006. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	.;.;.;D;.;.;.;D;D;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;.;.;D;.;.;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	4.3	.;.;.;H;.;H;.;H;H;.;H;.;H
PhyloP100		9.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	.;.;.;.;.;D;.;D;.;.;.;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;.;.;.;D;.;D;.;.;.;.;D
Sift4G	Uncertain	0.0020	.;.;.;.;.;D;.;D;.;.;.;.;D
Polyphen		1.0	.;D;.;D;D;D;D;D;D;D;D;.;D
Vest4		0.98, 0.97, 0.99
MutPred		0.94		Loss of ubiquitination at K465 (P = 0.0801);.;.;Loss of ubiquitination at K465 (P = 0.0801);.;Loss of ubiquitination at K465 (P = 0.0801);.;Loss of ubiquitination at K465 (P = 0.0801);Loss of ubiquitination at K465 (P = 0.0801);.;Loss of ubiquitination at K465 (P = 0.0801);.;Loss of ubiquitination at K465 (P = 0.0801);
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs797045041; hg19: chr21-38877746; COSMIC: COSV58292419; COSMIC: COSV58292419;