NM_001347721.2:c.1249A>T

Variant names:

• chr21-37505319-A-T
• rs748516503
• NM_001347721.2:c.1249A>T
• DYRK1A p.Ile417Phe

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.1249A>T (p.Ile417Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,162 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.24). 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DYRK1A NM_001347721.2 missense
• Predictors: REVEL: 0.36: Uncertain
• 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: 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		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000147 — very rare for AD/XL gene (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.1249A>T p.Ile417Phe	missense	Exon 10 of 12	Prot: NP_001334650.1 UniProt:
	DYRK1A NM_001396.5		c.1276A>T p.Ile426Phe	missense	Exon 10 of 12	Prot: NP_001387.2
	DYRK1A NM_001347722.2		c.1249A>T p.Ile417Phe	missense	Exon 10 of 12	Prot: NP_001334651.1 UniProt:

DYRK1A NM_001347721.2

MANE Select

HGVSc / HGVSpc.1249A>Tp.Ile417Phe

Exon rankExon 10 of 12

missense

Prot: NP_001334650.1UniProt: Q13627-2

DYRK1A NM_001396.5

HGVSc / HGVSpc.1276A>Tp.Ile426Phe

Exon rankExon 10 of 12

missense

Prot: NP_001387.2

DYRK1A NM_001347722.2

HGVSc / HGVSpc.1249A>Tp.Ile417Phe

Exon rankExon 10 of 12

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.1249A>T p.Ile417Phe	missense	Exon 10 of 12	Prot: ENSP00000494572.1 UniProt:
	DYRK1A ENST00000398960.7	TSL:1	c.1276A>T p.Ile426Phe	missense	Exon 10 of 12	Prot: ENSP00000381932.2 UniProt:
	DYRK1A ENST00000338785.8	TSL:1	c.1276A>T p.Ile426Phe	missense	Exon 11 of 13	Prot: ENSP00000342690.3 UniProt:

DYRK1A ENST00000647188.2

MANE Select

HGVSc / HGVSpc.1249A>Tp.Ile417Phe

Exon rankExon 10 of 12

missense

Prot: ENSP00000494572.1UniProt: Q13627-2

DYRK1A ENST00000398960.7

TSL:1

HGVSc / HGVSpc.1276A>Tp.Ile426Phe

Exon rankExon 10 of 12

missense

Prot: ENSP00000381932.2UniProt: Q13627-1

DYRK1A ENST00000338785.8

TSL:1

HGVSc / HGVSpc.1276A>Tp.Ile426Phe

Exon rankExon 11 of 13

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152162	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152162	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
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
FuncVEP CTI	Benign	0.24
GPN-Star LLR	N/A	-9.4
GPN-Star score	N/A	9.4
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.59	T
Mutation Taster	N/A	28/72	disease causing
MutationAssessor	Benign	1.2	L
PhyloP100	Uncertain	7.2
popEVE	Benign	-3.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0040	D
Varity_R	N/A	0.78
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs748516503;

hg19: chr21-38877622;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar