rs12483205

Variant names:

• chr21-37368522-A-G
• rs12483205
• NM_001347721.2:c.-77+894A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001347721.2(DYRK1A):​c.-77+894A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,162 control chromosomes in the GnomAD database, including 3,766 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3766 hom., cov: 32)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.625
• Publications: 20 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.-77+894A>G		intron_variant	Intron 1 of 11	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.-77+894A>G		intron_variant	Intron 1 of 11		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33007 AN: 152044 Hom.: 3765 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.0770

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.217 AC: 33030 AN: 152162 Hom.: 3766 Cov.: 32 AF XY: 0.215 AC XY: 16027 AN XY: 74374

African (AFR) AF: 0.219 AC: 9095 AN: 41508

American (AMR) AF: 0.181 AC: 2769 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 647 AN: 3470

East Asian (EAS) AF: 0.0769 AC: 399 AN: 5186

South Asian (SAS) AF: 0.110 AC: 530 AN: 4826

European-Finnish (FIN) AF: 0.288 AC: 3040 AN: 10564

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15761 AN: 67998

Other (OTH) AF: 0.192 AC: 406 AN: 2110

Alfa AF: 0.221 Hom.: 10759

Bravo AF: 0.212

Asia WGS AF: 0.0980 AC: 342 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.9
DANN	Benign	0.64
PhyloP100		0.63
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12483205; hg19: chr21-38740824;