rs140466090

chr21-37478168-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000398960.7(DYRK1A):c.208-13C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,610,834 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (23 hom.)
• Consequence: DYRK1A ENST00000398960.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.70

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 21-37478168-C-G is Benign according to our data. Variant chr21-37478168-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 376936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-37478168-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00299 (456/152338) while in subpopulation NFE AF= 0.00432 (294/68036). AF 95% confidence interval is 0.00391. There are 0 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 456 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2	c.208-40C>G		intron_variant		ENST00000647188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2	c.208-40C>G		intron_variant			NM_001347721.2	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00322 AC: 798 AN: 247774 Hom.: 3 AF XY: 0.00328 AC XY: 440 AN XY: 133980

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00776

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00198

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00400 AC: 5830 AN: 1458496 Hom.: 23 Cov.: 30 AF XY: 0.00397 AC XY: 2880 AN XY: 725536

Gnomad4 AFR exome AF: 0.000964

Gnomad4 AMR exome AF: 0.00214

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00450

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00276 AC XY: 206 AN XY: 74504

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00432

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00359 Hom.: 0

Bravo AF: 0.00296

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 12, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

DYRK1A-related intellectual disability syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs140466090; hg19: chr21-38850470;