rs968549141

chr21-37472776-C-Achr21-37472776-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001347721.2(DYRK1A):c.103C>A(p.Pro35Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P35S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DYRK1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.17498678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2	c.103C>A	p.Pro35Thr	missense_variant	3/12	ENST00000647188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2	c.103C>A	p.Pro35Thr	missense_variant	3/12		NM_001347721.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.;D;.;.;D;.;D;D;.;D;D;D;.;D;D;D;D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
Polyphen		0.14, 0.084, 0.042	.;B;.;B;B;B;B;.;.;B;B;B;.;.;B;.;.;B
Vest4		0.43, 0.36, 0.28, 0.37
MutPred		0.15		Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);.;Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);Gain of phosphorylation at P35 (P = 0.0336);.;.;Gain of phosphorylation at P35 (P = 0.0336);.;.;Gain of phosphorylation at P35 (P = 0.0336);
MVP		0.69
MPC		1.2
ClinPred		0.58	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.48

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: rs968549141; hg19: chr21-38845078;