NM_001347721.2:c.-324A>C

Variant names:

• chr21-37367381-A-C
• rs143156892
• NM_001347721.2:c.-324A>C

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.-324A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 148,502 control chromosomes in the GnomAD database, including 1,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1401 hom., cov: 32)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: DYRK1A NM_001347721.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.811
• 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=-0.91).
• BP6: Variant 21-37367381-A-C is Benign according to our data. Variant chr21-37367381-A-C is described in ClinVar as Benign. ClinVar VariationId is 1249958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 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.-324A>C		5_prime_UTR	Exon 1 of 12	NP_001334650.1	Q13627-2
	DYRK1A	NM_001347723.2		c.-325A>C		5_prime_UTR	Exon 1 of 11	NP_001334652.1	A0A2R8Y6I6
	DYRK1A	NM_001396.5		c.-77+1547A>C		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.-324A>C		5_prime_UTR	Exon 1 of 12	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000644942.1		c.-324A>C		5_prime_UTR	Exon 1 of 12	ENSP00000494544.1	Q13627-1
	DYRK1A	ENST00000647504.1		c.-325A>C		5_prime_UTR	Exon 1 of 11	ENSP00000495571.1	A0A2R8Y6I6

Frequencies

GnomAD3 genomes AF: 0.127 AC: 18829 AN: 148380 Hom.: 1400 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0773

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0238

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0929

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.143 AC: 2 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 1 AN XY: 8

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) AF: 0.500 AC: 1 AN: 2

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.100 AC: 1 AN: 10

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.127 AC: 18835 AN: 148488 Hom.: 1401 Cov.: 32 AF XY: 0.128 AC XY: 9297 AN XY: 72410

African (AFR) AF: 0.0883 AC: 3618 AN: 40976

American (AMR) AF: 0.0771 AC: 1159 AN: 15030

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 358 AN: 3420

East Asian (EAS) AF: 0.0239 AC: 119 AN: 4976

South Asian (SAS) AF: 0.103 AC: 493 AN: 4800

European-Finnish (FIN) AF: 0.218 AC: 2059 AN: 9442

Middle Eastern (MID) AF: 0.100 AC: 29 AN: 290

European-Non Finnish (NFE) AF: 0.161 AC: 10696 AN: 66584

Other (OTH) AF: 0.103 AC: 213 AN: 2066

Alfa AF: 0.147 Hom.: 226

Bravo AF: 0.114

Asia WGS AF: 0.0490 AC: 154 AN: 3144

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	-0.91
CADD	Benign	14
DANN	Benign	0.26
PhyloP100		-0.81
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

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

Other links and lift over

dbSNP: rs143156892; hg19: chr21-38739683;