21-37505319-ATT-GTC

Variant names:

• chr21-37505319-ATT-GTC
• NM_001347721.2:c.1249_1251delATTinsGTC
• DYRK1A p.Ile417Val

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001347721.2(DYRK1A):c.1249_1251delATTinsGTC (p.Ile417Val) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.95). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I417S: Likely_benign (ClinVar VariationId 833966, 1 star)

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.000157 by highest known P/LP ClinVar AF 0.000157) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	DYRK1A NM_001347721.2	MANE Select	c.1249_1251delATTinsGTC p.Ile417Val	missense	N/A	Prot: NP_001334650.1 UniProt:
	DYRK1A NM_001396.5		c.1276_1278delATTinsGTC p.Ile426Val	missense	N/A	Prot: NP_001387.2
	DYRK1A NM_001347722.2		c.1249_1251delATTinsGTC p.Ile417Val	missense	N/A	Prot: NP_001334651.1 UniProt:

DYRK1A NM_001347721.2

MANE Select

HGVSc / HGVSpc.1249_1251delATTinsGTCp.Ile417Val

Exon rankN/A

missense

Prot: NP_001334650.1UniProt: Q13627-2

DYRK1A NM_001396.5

HGVSc / HGVSpc.1276_1278delATTinsGTCp.Ile426Val

Exon rankN/A

missense

Prot: NP_001387.2

DYRK1A NM_001347722.2

HGVSc / HGVSpc.1249_1251delATTinsGTCp.Ile417Val

Exon rankN/A

missense

Prot: NP_001334651.1UniProt: Q13627-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	DYRK1A ENST00000647188.2	MANE Select	c.1249_1251delATTinsGTC p.Ile417Val	missense	N/A	Prot: ENSP00000494572.1 UniProt:
	DYRK1A ENST00000398960.7	TSL:1	c.1276_1278delATTinsGTC p.Ile426Val	missense	N/A	Prot: ENSP00000381932.2 UniProt:
	DYRK1A ENST00000338785.8	TSL:1	c.1276_1278delATTinsGTC p.Ile426Val	missense	N/A	Prot: ENSP00000342690.3 UniProt:

DYRK1A ENST00000647188.2

MANE Select

HGVSc / HGVSpc.1249_1251delATTinsGTCp.Ile417Val

Exon rankN/A

missense

Prot: ENSP00000494572.1UniProt: Q13627-2

DYRK1A ENST00000398960.7

TSL:1

HGVSc / HGVSpc.1276_1278delATTinsGTCp.Ile426Val

Exon rankN/A

missense

Prot: ENSP00000381932.2UniProt: Q13627-1

DYRK1A ENST00000338785.8

TSL:1

HGVSc / HGVSpc.1276_1278delATTinsGTCp.Ile426Val

Exon rankN/A

missense

Prot: ENSP00000342690.3UniProt: Q13627-5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr21-38877622;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar