NM_001347721.2:c.924+4_924+7delAGTA

Variant names:

• chr21-37490461-GGTAA-G
• rs1555984461
• NM_001347721.2:c.924+4_924+7delAGTA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_001347721.2(DYRK1A):​c.924+4_924+7delAGTA variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000660433: RT-PCR and sequencing of the mRNA derived from the individual with this variant showed exon 7 skipping (PMID:26922654).; SCV000709803: Functional studies demonstrate abnormal gene splicing with skipping of exon 6 (Luco et al., 2016)".

• Frequency: Genomes: not found (cov: 30)
• Consequence: DYRK1A NM_001347721.2 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.95
• Publications: 0 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000660433: RT-PCR and sequencing of the mRNA derived from the individual with this variant showed exon 7 skipping (PMID: 26922654).; SCV000709803: Functional studies demonstrate abnormal gene splicing with skipping of exon 6 (Luco et al., 2016)
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 21-37490461-GGTAA-G is Pathogenic according to our data. Variant chr21-37490461-GGTAA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 435011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.924+4_924+7delAGTA		splice_region intron	N/A	NP_001334650.1	Q13627-2
	DYRK1A	NM_001396.5		c.951+4_951+7delAGTA		splice_region intron	N/A	NP_001387.2
	DYRK1A	NM_001347722.2		c.924+4_924+7delAGTA		splice_region 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.924+1_924+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000398960.7	TSL:1	c.951+1_951+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000381932.2	Q13627-1
	DYRK1A	ENST00000338785.8	TSL:1	c.951+1_951+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000342690.3	Q13627-5

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	DYRK1A-related intellectual disability syndrome (5)
2	-	-	not provided (2)
1	-	-	Complex neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 0

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

Other links and lift over

dbSNP: rs1555984461; hg19: chr21-38862763;