21-37472046-T-C

Variant names:

• chr21-37472046-T-C
• rs2835761
• NM_001347721.2:c.11-638T>C

Variant summary

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

The NM_001347721.2(DYRK1A):​c.11-638T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 152,242 control chromosomes in the GnomAD database, including 59,650 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 0.88 (59650 hom., cov: 32)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347721.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	NM_001347721.2	MANE Select	c.11-638T>C		intron	N/A	NP_001334650.1
	DYRK1A	NM_001396.5		c.11-638T>C		intron	N/A	NP_001387.2
	DYRK1A	NM_001347722.2		c.11-638T>C		intron	N/A	NP_001334651.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.11-638T>C		intron	N/A	ENSP00000494572.1
	DYRK1A	ENST00000398960.7	TSL:1	c.11-638T>C		intron	N/A	ENSP00000381932.2
	DYRK1A	ENST00000338785.8	TSL:1	c.11-638T>C		intron	N/A	ENSP00000342690.3

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134364 AN: 152124 Hom.: 59595 Cov.: 32

Gnomad AFR AF: 0.945

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.884

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.867

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

GnomAD4 genome AF: 0.883 AC: 134479 AN: 152242 Hom.: 59650 Cov.: 32 AF XY: 0.885 AC XY: 65899 AN XY: 74436

African (AFR) AF: 0.945 AC: 39277 AN: 41548

American (AMR) AF: 0.887 AC: 13568 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2780 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5172 AN: 5188

South Asian (SAS) AF: 0.882 AC: 4257 AN: 4824

European-Finnish (FIN) AF: 0.864 AC: 9151 AN: 10594

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.843 AC: 57364 AN: 68008

Other (OTH) AF: 0.869 AC: 1831 AN: 2108

Alfa AF: 0.876 Hom.: 16769

Bravo AF: 0.891

Asia WGS AF: 0.943 AC: 3282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.98
DANN	Benign	0.45
PhyloP100		-1.3
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: rs2835761; hg19: chr21-38844348;