chr21-37505500-G-A

Position:

• chr21-37505500-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001347721.2(DYRK1A):​c.1430G>A​(p.Gly477Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYRK1A. . Gene score misZ 3.3441 (greater than the threshold 3.09). Trascript score misZ 4.1103 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, DYRK1A-related intellectual disability syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.1430G>A	p.Gly477Asp	missense_variant	10/12	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.1430G>A	p.Gly477Asp	missense_variant	10/12		NM_001347721.2	ENSP00000494572	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability syndrome due to a DYRK1A point mutation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Nov 20, 2017

This de novo variant in DYRK1A was identified in a young male patient with ASD, learning disorder and macrocephaly -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;.;.;D;.;.;.;D;D;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;.;.;D;.;.;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.55	.;.;.;N;.;N;.;N;N;.;N;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.4	.;.;.;.;.;N;.;D;.;.;.;.;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.013	.;.;.;.;.;D;.;D;.;.;.;.;D
Sift4G	Benign	0.19	.;.;.;.;.;T;.;T;.;.;.;.;T
Polyphen		0.96, 0.94, 1.0	.;D;.;P;D;D;D;P;P;D;D;.;D
Vest4		0.78, 0.91, 0.79
MutPred		0.33		Gain of solvent accessibility (P = 0.008);.;.;Gain of solvent accessibility (P = 0.008);.;Gain of solvent accessibility (P = 0.008);.;Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);.;Gain of solvent accessibility (P = 0.008);.;Gain of solvent accessibility (P = 0.008);
MVP		0.75
MPC		2.0
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.58
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555991030; hg19: chr21-38877803;