21-37472458-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001347721.2(DYRK1A):c.11-226T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,294 control chromosomes in the GnomAD database, including 1,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.10 (1116 hom., cov: 32)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.575

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-37472458-T-A is Benign according to our data. Variant chr21-37472458-T-A is described in ClinVar as [Benign]. Clinvar id is 681714.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2	c.11-226T>A		intron_variant		ENST00000647188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2	c.11-226T>A		intron_variant			NM_001347721.2	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15901 AN: 152176 Hom.: 1116 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0242

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.0828

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.104 AC: 15896 AN: 152294 Hom.: 1116 Cov.: 32 AF XY: 0.105 AC XY: 7826 AN XY: 74462

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.0654

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.0243

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.0819

Alfa AF: 0.131 Hom.: 191

Bravo AF: 0.0928

Asia WGS AF: 0.0460 AC: 160 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	12
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs17229402; hg19: chr21-38844760;