NM_001347721.2:c.-76-1479G>A

Variant names:

• chr21-37418820-G-A
• rs116906519
• NM_001347721.2:c.-76-1479G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2654 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347721.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	NM_001347721.2	MANE Select	c.-76-1479G>A		intron	N/A	NP_001334650.1	Q13627-2
	DYRK1A	NM_001396.5		c.-76-1479G>A		intron	N/A	NP_001387.2
	DYRK1A	NM_001347722.2		c.-76-1479G>A		intron	N/A	NP_001334651.1	Q13627-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.-76-1479G>A		intron	N/A	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000398960.7	TSL:1	c.-76-1479G>A		intron	N/A	ENSP00000381932.2	Q13627-1
	DYRK1A	ENST00000338785.8	TSL:1	c.-76-1479G>A		intron	N/A	ENSP00000342690.3	Q13627-5

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

African (AFR) AF: 0.00460 AC: 191 AN: 41526

American (AMR) AF: 0.0105 AC: 160 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0253 AC: 122 AN: 4822

European-Finnish (FIN) AF: 0.0313 AC: 331 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1703 AN: 68004

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.0205 Hom.: 21

Bravo AF: 0.0160

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.17
DANN	Benign	0.59
PhyloP100		-1.0
PromoterAI		-0.050	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs116906519; hg19: chr21-38791122;