chr21-37367381-A-C

Position:

• chr21-37367381-A-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.-324A>C		5_prime_UTR_variant	1/12	ENST00000647188.2	NP_001334650.1
DYRK1A	NM_001347723.2	c.-325A>C		5_prime_UTR_variant	1/11		NP_001334652.1
DYRK1A	NM_001396.5	c.-77+1547A>C		intron_variant			NP_001387.2
DYRK1A	NM_001347722.2	c.-77+1196A>C		intron_variant			NP_001334651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188	c.-324A>C		5_prime_UTR_variant	1/12		NM_001347721.2	ENSP00000494572.1

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

Gnomad4 SAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.100

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

Gnomad4 AFR AF: 0.0883

Gnomad4 AMR AF: 0.0771

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0239

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.103

Alfa AF: 0.147 Hom.: 226

Bravo AF: 0.114

Asia WGS AF: 0.0490 AC: 154 AN: 3144

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	14
DANN	Benign	0.26
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

Publications

LitVar

Other links and lift over

dbSNP: rs143156892; hg19: chr21-38739683;