NM_001347721.2:c.953A>T

Variant names:

• chr21-37493045-A-T
• rs1555985554
• NM_001347721.2:c.953A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Strong

The NM_001347721.2(DYRK1A):​c.953A>T​(p.Tyr318Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. Y318C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 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: Likely_pathogenic. The variant received 8 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, 6 uncertain in NM_001347721.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-37493045-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438288.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347721.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	NM_001347721.2	MANE Select	c.953A>T	p.Tyr318Phe	missense	Exon 8 of 12	NP_001334650.1
	DYRK1A	NM_001396.5		c.980A>T	p.Tyr327Phe	missense	Exon 8 of 12	NP_001387.2
	DYRK1A	NM_001347722.2		c.953A>T	p.Tyr318Phe	missense	Exon 8 of 12	NP_001334651.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.953A>T	p.Tyr318Phe	missense	Exon 8 of 12	ENSP00000494572.1
	DYRK1A	ENST00000398960.7	TSL:1	c.980A>T	p.Tyr327Phe	missense	Exon 8 of 12	ENSP00000381932.2
	DYRK1A	ENST00000338785.8	TSL:1	c.980A>T	p.Tyr327Phe	missense	Exon 9 of 13	ENSP00000342690.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 148940 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000472 AC: 577 AN: 1223666 Hom.: 0 Cov.: 29 AF XY: 0.000464 AC XY: 285 AN XY: 614232

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000392 AC: 11 AN: 28068

American (AMR) AF: 0.000263 AC: 11 AN: 41828

Ashkenazi Jewish (ASJ) AF: 0.000599 AC: 13 AN: 21720

East Asian (EAS) AF: 0.000517 AC: 17 AN: 32864

South Asian (SAS) AF: 0.000146 AC: 12 AN: 82078

European-Finnish (FIN) AF: 0.000247 AC: 11 AN: 44526

Middle Eastern (MID) AF: 0.000599 AC: 3 AN: 5010

European-Non Finnish (NFE) AF: 0.000522 AC: 479 AN: 918204

Other (OTH) AF: 0.000405 AC: 20 AN: 49368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 149076 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72872

African (AFR) AF: 0.00 AC: 0 AN: 40850

American (AMR) AF: 0.00 AC: 0 AN: 14878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 4618

South Asian (SAS) AF: 0.00 AC: 0 AN: 4206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67426

Other (OTH) AF: 0.00 AC: 0 AN: 2108

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.96		Gain of sheet (P = 0.1208)
MVP		0.77
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.81
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 12

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

Other links and lift over

dbSNP: rs1555985554; hg19: chr21-38865347;