chr21-37419234-A-G

Variant names:

• chr21-37419234-A-G
• rs17814675
• NM_001347721.2:c.-76-1065A>G

Variant summary

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

The NM_130436.2(DYRK1A):​c.-1141A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,206 control chromosomes in the GnomAD database, including 1,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1301 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: DYRK1A NM_130436.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.309
• Publications: 6 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=-0.87).
• BP6: Variant 21-37419234-A-G is Benign according to our data. Variant chr21-37419234-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130436.2. 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.-76-1065A>G		intron	N/A	NP_001334650.1	Q13627-2
	DYRK1A	NM_130436.2		c.-1141A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_569120.1	Q13627-2
	DYRK1A	NM_130436.2		c.-1141A>G		5_prime_UTR	Exon 1 of 11	NP_569120.1	Q13627-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.-76-1065A>G		intron	N/A	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000398960.7	TSL:1	c.-76-1065A>G		intron	N/A	ENSP00000381932.2	Q13627-1
	DYRK1A	ENST00000338785.8	TSL:1	c.-76-1065A>G		intron	N/A	ENSP00000342690.3	Q13627-5

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16918 AN: 152086 Hom.: 1301 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.0883

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.111 AC: 16912 AN: 152204 Hom.: 1301 Cov.: 32 AF XY: 0.113 AC XY: 8431 AN XY: 74416

African (AFR) AF: 0.0297 AC: 1235 AN: 41558

American (AMR) AF: 0.0697 AC: 1065 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3472

East Asian (EAS) AF: 0.0218 AC: 113 AN: 5174

South Asian (SAS) AF: 0.104 AC: 500 AN: 4822

European-Finnish (FIN) AF: 0.218 AC: 2310 AN: 10592

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10972 AN: 67990

Other (OTH) AF: 0.0874 AC: 185 AN: 2116

Alfa AF: 0.135 Hom.: 2332

Bravo AF: 0.0965

Asia WGS AF: 0.0450 AC: 156 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	5.2
DANN	Benign	0.72
PhyloP100		0.31
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17814675; hg19: chr21-38791536;