rs797044520

chr21-37505442-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.1372C>T(p.Arg458Ter) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYRK1A NM_001347721.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.09

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]

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 21-37505442-C-T is Pathogenic according to our data. Variant chr21-37505442-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 204005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-37505442-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2	c.1372C>T	p.Arg458Ter	stop_gained	10/12	ENST00000647188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2	c.1372C>T	p.Arg458Ter	stop_gained	10/12		NM_001347721.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Sep 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2012	This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 18-year-old male with austistic spectrum, moderate intellectual disability, hypotonia, spasticity and ataxia, knee contractures, seizures, dysmorphisms, tall stature, hallux valgus, microcephaly, optic nerve pallor, orchiopexy/inguinal hernia repaired, dermoid or pilomatrixoma spontaneously resolved -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Aug 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 16, 2023	This sequence change creates a premature translational stop signal (p.Arg467*) 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 conditions (PMID: 25944381). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 204005). For these reasons, this variant has been classified as Pathogenic. -

DYRK1A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This nonsense variant occurs in exon 9 of 11 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously identified in multiple individuals with developmental regression, microcephaly, intellectual disability, global developmental delay, severe speech delay, seizures, feeding difficulties, and autism spectrum disorder (PMID: 26677511, 30831192, 25944381). Loss-of-function variation is an established mechanism of disease for DYRK1A-related disorders (PMID: 26677511). The c.1399C>T (p.Arg467Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1399C>T (p.Arg467Ter) variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34345024, 26633545, 31263215, 25944381, 31216405, 30831192) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.95, 0.99, 0.98
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs797044520; hg19: chr21-38877745; COSMIC: COSV58296731; COSMIC: COSV58296731;