21-37419234-A-G

Position:

• chr21-37419234-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.87).
• BP6: Variant 21-37419234-A-G is Benign according to our data. Variant chr21-37419234-A-G is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.-76-1065A>G		intron_variant		ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.-76-1065A>G		intron_variant			NM_001347721.2	ENSP00000494572.1

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

Gnomad4 NFE exome AF: 0.500

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

Gnomad4 AFR AF: 0.0297

Gnomad4 AMR AF: 0.0697

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0218

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.0874

Alfa AF: 0.144 Hom.: 1684

Bravo AF: 0.0965

Asia WGS AF: 0.0450 AC: 156 AN: 3478

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 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.2
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17814675; hg19: chr21-38791536;