chr21-37367544-C-T

Variant names:

• chr21-37367544-C-T
• rs28565161
• NM_001347721.2:c.-161C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001347721.2(DYRK1A):​c.-161C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 147,050 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (304 hom., cov: 32)
  • Exomes 𝑓: 0.056 (1 hom.)
• Consequence: DYRK1A NM_001347721.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.174
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 21-37367544-C-T is Benign according to our data. Variant chr21-37367544-C-T is described in ClinVar as Benign. ClinVar VariationId is 1296230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0598 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	NM_001347721.2	MANE Select	c.-161C>T		5_prime_UTR	Exon 1 of 12	NP_001334650.1	Q13627-2
	DYRK1A	NM_001347723.2		c.-162C>T		5_prime_UTR	Exon 1 of 11	NP_001334652.1	A0A2R8Y6I6
	DYRK1A	NM_001396.5		c.-77+1710C>T		intron	N/A	NP_001387.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.-161C>T		5_prime_UTR	Exon 1 of 12	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000644942.1		c.-161C>T		5_prime_UTR	Exon 1 of 12	ENSP00000494544.1	Q13627-1
	DYRK1A	ENST00000647504.1		c.-162C>T		5_prime_UTR	Exon 1 of 11	ENSP00000495571.1	A0A2R8Y6I6

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 8785 AN: 146338 Hom.: 300 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.00449

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0650

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.141

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0832

GnomAD4 exome AF: 0.0556 AC: 34 AN: 612 Hom.: 1 Cov.: 0 AF XY: 0.0515 AC XY: 21 AN XY: 408

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.167 AC: 1 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.154 AC: 4 AN: 26

South Asian (SAS) AF: 0.0326 AC: 3 AN: 92

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.0541 AC: 25 AN: 462

Other (OTH) AF: 0.00 AC: 0 AN: 14

GnomAD4 genome AF: 0.0601 AC: 8798 AN: 146438 Hom.: 304 Cov.: 32 AF XY: 0.0587 AC XY: 4193 AN XY: 71378

African (AFR) AF: 0.0619 AC: 2503 AN: 40458

American (AMR) AF: 0.0594 AC: 884 AN: 14874

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 525 AN: 3402

East Asian (EAS) AF: 0.0650 AC: 318 AN: 4890

South Asian (SAS) AF: 0.0420 AC: 199 AN: 4738

European-Finnish (FIN) AF: 0.0314 AC: 284 AN: 9044

Middle Eastern (MID) AF: 0.137 AC: 39 AN: 284

European-Non Finnish (NFE) AF: 0.0589 AC: 3875 AN: 65828

Other (OTH) AF: 0.0823 AC: 167 AN: 2030

Alfa AF: 0.0521 Hom.: 23

Asia WGS AF: 0.0570 AC: 171 AN: 2978

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		0.17
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.5

Splicing

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

Other links and lift over

dbSNP: rs28565161; hg19: chr21-38739846;