ENST00000455097:c.-219A>T

Variant names:

• chr21-37420375-A-T
• ENST00000455097:c.-219A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The ENST00000455097(DYRK1A):​c.-219A>T variant causes a 5 prime UTR premature start codon gain change. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYRK1A ENST00000455097 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P: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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 21-37420375-A-T is Pathogenic according to our data. Variant chr21-37420375-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 3764212.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 12	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 12		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.20	.;.;T;.;.;.;.;T;T;T;.;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;.;.;.;D;.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.89	T
PROVEAN	Benign	0.19	.;.;.;.;N;.;.;N;N;N;.;.;N
REVEL	Uncertain	0.36
Sift	Benign	0.17	.;.;.;.;T;.;.;T;T;T;.;.;T
Sift4G	Benign	0.39	.;.;.;.;T;.;.;T;T;T;.;.;T
Polyphen		0.011, 0.0060	.;B;B;B;B;B;.;.;B;B;B;B;B
Vest4		0.81, 0.83, 0.90, 0.81
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);Gain of catalytic residue at M1 (P = 0.1214);
MVP		0.94
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.17
gMVP		0.29

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: chr21-38792677;