21-37420381-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_001347721.2(DYRK1A):c.7A>G(p.Thr3Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.55

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 Likely_benign. 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=0.17144871).
• BP6: Variant 21-37420381-A-G is Benign according to our data. Variant chr21-37420381-A-G is described in ClinVar as [Benign]. Clinvar id is 1601373.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2	c.7A>G	p.Thr3Ala	missense_variant	2/12	ENST00000647188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2	c.7A>G	p.Thr3Ala	missense_variant	2/12		NM_001347721.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;.;.;.;T;.;T;T;.;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
Polyphen		0.59, 0.46	.;P;P;P;P;P;.;.;P;P;P;P;P
Vest4		0.42, 0.56, 0.36, 0.37
MutPred		0.072		Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);Loss of phosphorylation at T3 (P = 0.0284);
MVP		0.77
MPC		1.1
ClinPred		0.66	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38792683;