NM_001347721.2:c.11-21726A>G

Variant names:

• chr21-37450958-A-G
• rs1137600
• NM_001347721.2:c.11-21726A>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.11-21726A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,036 control chromosomes in the GnomAD database, including 6,937 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 0.30 (6937 hom., cov: 32)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.429
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.11-21726A>G		intron_variant	Intron 2 of 11	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.11-21726A>G		intron_variant	Intron 2 of 11		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45502 AN: 151918 Hom.: 6930 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.300 AC: 45538 AN: 152036 Hom.: 6937 Cov.: 32 AF XY: 0.302 AC XY: 22457 AN XY: 74310

African (AFR) AF: 0.308 AC: 12762 AN: 41452

American (AMR) AF: 0.269 AC: 4108 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 703 AN: 3468

East Asian (EAS) AF: 0.363 AC: 1878 AN: 5174

South Asian (SAS) AF: 0.378 AC: 1820 AN: 4812

European-Finnish (FIN) AF: 0.343 AC: 3627 AN: 10574

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19664 AN: 67958

Other (OTH) AF: 0.301 AC: 634 AN: 2106

Alfa AF: 0.305 Hom.: 965

Bravo AF: 0.295

Asia WGS AF: 0.378 AC: 1316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.52
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1137600; hg19: chr21-38823260;