rs1555985649

Positions:

• chr21-37493102-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

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
DYRK1A	NM_001347721.2	c.1010C>T	p.Ser337Phe	missense_variant	8/12	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.1010C>T	p.Ser337Phe	missense_variant	8/12		NM_001347721.2	ENSP00000494572.1

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

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 19, 2016	The 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 submitter	clinical testing	Illumina Laboratory Services, Illumina	May 09, 2023	The 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

Other links and lift over

dbSNP: rs1555985649; hg19: chr21-38865404;