rs797044526

Variant names:

• chr21-37490393-C-T
• rs797044526
• NM_001347721.2:c.856C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001347721.2(DYRK1A):​c.856C>T​(p.Leu286Phe) 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 (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.87
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• DYRK1A-related intellectual disability syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001347721.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 21-37490393-C-T is Pathogenic according to our data. Variant chr21-37490393-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 204011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.856C>T	p.Leu286Phe	missense_variant	Exon 7 of 12	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.856C>T	p.Leu286Phe	missense_variant	Exon 7 of 12		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Pathogenic:1

Sep 15, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Feb 12, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L295F pathogenic variant in the DYRK1A gene has been reported previously as an assumed de novo variant in an individual with congenital microcephaly, feeding difficulties, short stature, dysmorphic features, mild global developmental delay including severe speech delay, skeletal anomalies, blepharophimosis, abnormal gait, hand stereotypies, and duodenal atresia (Ji et al., 2015). The L295F variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L295F variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L295F as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	.;.;.;T;.;.;.;T;T;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;.;D;.;.;D;.;.;D;D;.;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.062	D
MutationAssessor	Benign	1.8	.;.;.;L;.;L;.;L;L;.;.;L;.;.;L
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	.;.;.;.;.;D;.;D;.;.;.;.;.;.;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;.;.;.;.;D;.;D;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0020	.;.;.;.;.;D;.;D;.;.;.;.;.;.;D
Polyphen		1.0	.;D;.;D;D;D;D;D;D;D;.;D;.;.;D
Vest4		0.84, 0.86, 0.80
MutPred		0.79		Loss of catalytic residue at L295 (P = 0.0651);.;.;Loss of catalytic residue at L295 (P = 0.0651);.;Loss of catalytic residue at L295 (P = 0.0651);.;Loss of catalytic residue at L295 (P = 0.0651);Loss of catalytic residue at L295 (P = 0.0651);.;.;Loss of catalytic residue at L295 (P = 0.0651);.;.;Loss of catalytic residue at L295 (P = 0.0651);
MVP		0.92
MPC		2.4
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs797044526; hg19: chr21-38862695;