rs369805539

Positions:

• chr21-37505285-G-C
• chr21-37505285-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001347721.2(DYRK1A):​c.1215G>C​(p.Glu405Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYRK1A NM_001347721.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17567319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.1215G>C	p.Glu405Asp	missense_variant, splice_region_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.1215G>C	p.Glu405Asp	missense_variant, splice_region_variant	10/12		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 2018

This sequence change replaces glutamic acid with aspartic acid at codon 414 of the DYRK1A protein (p.Glu414Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DYRK1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;.;.;T;.;.;.;T;T;.;.;.;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;.;D;.;.;D;.;.;D;D;.;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;.;.;L;.;L;.;L;L;.;.;L;.;.;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.78	.;.;.;.;.;N;.;N;.;.;.;.;.;.;N
REVEL	Benign	0.042
Sift	Benign	0.26	.;.;.;.;.;T;.;T;.;.;.;.;.;.;T
Sift4G	Benign	0.50	.;.;.;.;.;T;.;T;.;.;.;.;.;.;T
Polyphen		0.0, 0.048	.;B;.;B;B;B;B;B;B;B;.;B;.;.;B
Vest4		0.37, 0.37, 0.35
MutPred		0.24		Loss of methylation at K409 (P = 0.1312);.;.;Loss of methylation at K409 (P = 0.1312);.;Loss of methylation at K409 (P = 0.1312);.;Loss of methylation at K409 (P = 0.1312);Loss of methylation at K409 (P = 0.1312);.;.;Loss of methylation at K409 (P = 0.1312);.;.;Loss of methylation at K409 (P = 0.1312);
MVP		0.63
MPC		0.99
ClinPred		0.22	T
GERP RS		3.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.44
gMVP		0.42

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: rs369805539; hg19: chr21-38877588;