chr21-37410653-C-T

Variant names:

• chr21-37410653-C-T
• rs55839411
• ENST00000338785.8:c.-94C>T

Variant summary

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

The NM_101395.2(DYRK1A):​c.-94C>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 0.0364 in 152,328 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (150 hom., cov: 31)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: DYRK1A NM_101395.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70
• 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=-0.97).
• BP6: Variant 21-37410653-C-T is Benign according to our data. Variant chr21-37410653-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_101395.2. 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.-76-9646C>T		intron	N/A	NP_001334650.1	Q13627-2
	DYRK1A	NM_101395.2		c.-94C>T		5_prime_UTR	Exon 2 of 13	NP_567824.1	Q13627-5
	DYRK1A	NM_001396.5		c.-76-9646C>T		intron	N/A	NP_001387.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000338785.8	TSL:1	c.-94C>T		5_prime_UTR	Exon 2 of 13	ENSP00000342690.3	Q13627-5
	DYRK1A	ENST00000647188.2	MANE Select	c.-76-9646C>T		intron	N/A	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000398960.7	TSL:1	c.-76-9646C>T		intron	N/A	ENSP00000381932.2	Q13627-1

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5541 AN: 152148 Hom.: 150 Cov.: 31

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0427

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0387

GnomAD4 exome AF: 0.0161 AC: 1 AN: 62 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 52

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

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

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0208 AC: 1 AN: 48

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0364 AC: 5546 AN: 152266 Hom.: 150 Cov.: 31 AF XY: 0.0352 AC XY: 2623 AN XY: 74452

African (AFR) AF: 0.0101 AC: 419 AN: 41552

American (AMR) AF: 0.0427 AC: 653 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5176

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4830

European-Finnish (FIN) AF: 0.0414 AC: 439 AN: 10602

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0541 AC: 3677 AN: 68018

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0480 Hom.: 32

Bravo AF: 0.0360

Asia WGS AF: 0.0140 AC: 52 AN: 3478

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	-0.97
CADD	Benign	2.3
DANN	Benign	0.68
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs55839411; hg19: chr21-38782955;