chr21-37418820-G-A

Position:

• chr21-37418820-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001347721.2(DYRK1A):​c.-76-1479G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 152,178 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03

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=-0.9).
• BP6: Variant 21-37418820-G-A is Benign according to our data. Variant chr21-37418820-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 671429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0174 (2654/152178) while in subpopulation SAS AF= 0.0253 (122/4822). AF 95% confidence interval is 0.0241. There are 31 homozygotes in gnomad4. There are 1332 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2654 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2	c.-76-1479G>A		intron_variant		ENST00000647188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2	c.-76-1479G>A		intron_variant			NM_001347721.2	P1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2655 AN: 152060 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0105

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

GnomAD4 genome AF: 0.0174 AC: 2654 AN: 152178 Hom.: 31 Cov.: 32 AF XY: 0.0179 AC XY: 1332 AN XY: 74382

Gnomad4 AFR AF: 0.00460

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0201 Hom.: 5

Bravo AF: 0.0160

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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	-0.90
CADD	Benign	0.17
DANN	Benign	0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs116906519; hg19: chr21-38791122;