NM_001347721.2:c.1249A>T

Variant names:

• chr21-37505319-A-T
• rs748516503
• NM_001347721.2:c.1249A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001347721.2(DYRK1A):​c.1249A>T​(p.Ile417Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I417S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.24
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1249A>T	p.Ile417Phe	missense	Exon 10 of 12	NP_001334650.1	Q13627-2
	DYRK1A	NM_001396.5		c.1276A>T	p.Ile426Phe	missense	Exon 10 of 12	NP_001387.2
	DYRK1A	NM_001347722.2		c.1249A>T	p.Ile417Phe	missense	Exon 10 of 12	NP_001334651.1	Q13627-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.1249A>T	p.Ile417Phe	missense	Exon 10 of 12	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000398960.7	TSL:1	c.1276A>T	p.Ile426Phe	missense	Exon 10 of 12	ENSP00000381932.2	Q13627-1
	DYRK1A	ENST00000338785.8	TSL:1	c.1276A>T	p.Ile426Phe	missense	Exon 11 of 13	ENSP00000342690.3	Q13627-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.37	B
Vest4		0.74
MVP		0.74
MPC		2.2
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.78
Mutation Taster		=28/72	disease causing

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: rs748516503; hg19: chr21-38877622;