rs8132976

Variant names:

• chr21-37500748-C-A
• rs8132976
• NM_001347721.2:c.1212+4490C>A

Variant summary

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

The NM_001347721.2(DYRK1A):​c.1212+4490C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 151,552 control chromosomes in the GnomAD database, including 23,150 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 0.55 (23150 hom., cov: 31)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110
• Publications: 1 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.1212+4490C>A		intron_variant	Intron 9 of 11	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.1212+4490C>A		intron_variant	Intron 9 of 11		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82627 AN: 151432 Hom.: 23117 Cov.: 31

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.563

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

GnomAD4 genome AF: 0.546 AC: 82715 AN: 151552 Hom.: 23150 Cov.: 31 AF XY: 0.541 AC XY: 40121 AN XY: 74100

African (AFR) AF: 0.675 AC: 27907 AN: 41372

American (AMR) AF: 0.470 AC: 7158 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1724 AN: 3460

East Asian (EAS) AF: 0.433 AC: 2238 AN: 5166

South Asian (SAS) AF: 0.549 AC: 2646 AN: 4816

European-Finnish (FIN) AF: 0.510 AC: 5270 AN: 10330

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.502 AC: 34074 AN: 67852

Other (OTH) AF: 0.565 AC: 1193 AN: 2110

Alfa AF: 0.536 Hom.: 2783

Bravo AF: 0.547

Asia WGS AF: 0.512 AC: 1762 AN: 3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.94
DANN	Benign	0.35
PhyloP100		-0.011
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: rs8132976; hg19: chr21-38873051;