chr21-37436771-T-C

Variant names:

• chr21-37436771-T-C
• rs2835740
• NM_001347721.2:c.10+16387T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001347721.2(DYRK1A):​c.10+16387T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,144 control chromosomes in the GnomAD database, including 2,934 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2934 hom., cov: 32)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.256
• Publications: 6 publications found

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]

DYRK1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• DYRK1A-related intellectual disability syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.10+16387T>C		intron_variant	Intron 2 of 11	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.10+16387T>C		intron_variant	Intron 2 of 11		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28523 AN: 152024 Hom.: 2927 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.201

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

GnomAD4 genome AF: 0.188 AC: 28557 AN: 152144 Hom.: 2934 Cov.: 32 AF XY: 0.192 AC XY: 14246 AN XY: 74382

African (AFR) AF: 0.170 AC: 7058 AN: 41510

American (AMR) AF: 0.191 AC: 2923 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 534 AN: 3470

East Asian (EAS) AF: 0.363 AC: 1876 AN: 5170

South Asian (SAS) AF: 0.355 AC: 1712 AN: 4824

European-Finnish (FIN) AF: 0.186 AC: 1969 AN: 10590

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11884 AN: 67996

Other (OTH) AF: 0.207 AC: 436 AN: 2106

Alfa AF: 0.186 Hom.: 1504

Bravo AF: 0.186

Asia WGS AF: 0.361 AC: 1254 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.8
DANN	Benign	0.64
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2835740; hg19: chr21-38809073;