21-37493131-A-G

Variant names:

• chr21-37493131-A-G
• rs145857775
• NM_001347721.2:c.1039A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_001347721.2(DYRK1A):​c.1039A>G​(p.Thr347Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,524 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T347P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.32
• Publications: 10 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.017034084).
• BP6: Variant 21-37493131-A-G is Benign according to our data. Variant chr21-37493131-A-G is described in ClinVar as Benign. ClinVar VariationId is 383473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 268 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	NM_001347721.2	MANE Select	c.1039A>G	p.Thr347Ala	missense	Exon 8 of 12	NP_001334650.1	Q13627-2
	DYRK1A	NM_001396.5		c.1066A>G	p.Thr356Ala	missense	Exon 8 of 12	NP_001387.2
	DYRK1A	NM_001347722.2		c.1039A>G	p.Thr347Ala	missense	Exon 8 of 12	NP_001334651.1	Q13627-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.1039A>G	p.Thr347Ala	missense	Exon 8 of 12	ENSP00000494572.1	Q13627-2
	DYRK1A	ENST00000398960.7	TSL:1	c.1066A>G	p.Thr356Ala	missense	Exon 8 of 12	ENSP00000381932.2	Q13627-1
	DYRK1A	ENST00000338785.8	TSL:1	c.1066A>G	p.Thr356Ala	missense	Exon 9 of 13	ENSP00000342690.3	Q13627-5

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00195 AC: 489 AN: 251372 AF XY: 0.00188

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00156 AC: 2285 AN: 1461218 Hom.: 5 Cov.: 34 AF XY: 0.00149 AC XY: 1084 AN XY: 726876

African (AFR) AF: 0.000149 AC: 5 AN: 33462

American (AMR) AF: 0.000716 AC: 32 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.0124 AC: 663 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00135 AC: 1501 AN: 1111540

Other (OTH) AF: 0.00136 AC: 82 AN: 60336

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74466

African (AFR) AF: 0.000385 AC: 16 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00117 Hom.: 2

Bravo AF: 0.000801

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00155 AC: 188

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	DYRK1A-related intellectual disability syndrome (2)
-	-	2	not provided (2)
-	-	1	DYRK1A-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		0.98	D
Vest4		0.81
MVP		0.88
MPC		2.2
ClinPred		0.048	T
GERP RS		5.8
Varity_R		0.86
gMVP		0.91
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs145857775; hg19: chr21-38865433;