chr21-37493102-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001347721.2(DYRK1A):​c.1010C>T​(p.Ser337Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S337P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

DYRK1A
NM_001347721.2 missense

Scores

14
3
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.91
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-37493101-T-C is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYRK1A. . Gene score misZ 3.3441 (greater than the threshold 3.09). Trascript score misZ 4.1103 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, DYRK1A-related intellectual disability syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant 21-37493102-C-T is Pathogenic according to our data. Variant chr21-37493102-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYRK1ANM_001347721.2 linkuse as main transcriptc.1010C>T p.Ser337Phe missense_variant 8/12 ENST00000647188.2 NP_001334650.1 Q13627-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYRK1AENST00000647188.2 linkuse as main transcriptc.1010C>T p.Ser337Phe missense_variant 8/12 NM_001347721.2 ENSP00000494572.1 Q13627-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 19, 2016The p.Ser346Phe variant in DYRK1A was absent from large population studies and h as been detected in one individual with a range of phenotypic manifestations inc luding intellectual disability, seizures and microcephaly (TIDEX study, pers.com m.) It reportedly was not detected in the unaffected parents, which increases th e likelihood that it is pathogenic. A different amino acid change at the same po sition (p.Ser346Pro) has been identified as a de novo variant in 2 individuals w ith intellectual disability, autism, and microcephaly (Bronicki 2015, DDDS 2015) , further supporting that a change at this position may not be tolerated. This i s consistent with computational predictions that suggest an impact to the protei n. Finally, the DYRK1A gene is associated with "DYRK1A-related intellectual disa bility syndrome with all cases reported to date resulting from a de novo variant (https://www.ncbi.nlm.nih.gov/books/NBK333438/). In summary, the available evi dence suggests that the Ser346Phe variant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 09, 2023The DYRK1A c.1037C>T (p.Ser346Phe) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. However, a different amino acid substitution at the same codon (p.Ser346Pro) has been reported in individuals with DYRK1A-related intellectual disability syndrome (PMID: 25920557; 28053047; 29700199). The p.Ser346Phe variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant is located in the protein kinase domain of DYRK1A, and functional studies conducted in human cell lines demonstrated that the p.Ser346Phe and p.Ser346Pro variants abolish kinase activity (PMID: 29700199; 30831192). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant was identified in a de novo state. Based on the available evidence, the variant is classified as likely pathogenic for intellectual developmental disorder. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
.;.;.;D;.;.;.;D;D;.;.;.;.;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;.;D;.;.;D;.;.;D;D;.;D;D;D;D
M_CAP
Benign
0.059
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Pathogenic
4.6
.;.;.;H;.;H;.;H;H;.;.;H;.;.;H
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-6.0
.;.;.;.;.;D;.;D;.;.;.;.;.;.;D
REVEL
Pathogenic
0.75
Sift
Pathogenic
0.0
.;.;.;.;.;D;.;D;.;.;.;.;.;.;D
Sift4G
Pathogenic
0.0
.;.;.;.;.;D;.;D;.;.;.;.;.;.;D
Polyphen
1.0
.;D;.;D;D;D;D;D;D;D;.;D;.;.;D
Vest4
0.93, 0.98, 0.97
MutPred
0.88
Loss of helix (P = 0.2022);.;.;Loss of helix (P = 0.2022);.;Loss of helix (P = 0.2022);.;Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);.;.;Loss of helix (P = 0.2022);.;.;Loss of helix (P = 0.2022);
MVP
0.91
MPC
2.4
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.99
gMVP
0.99

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555985649; hg19: chr21-38865404; API