rs1057175147

Variant names:

• chr21-37472720-G-A
• rs1057175147
• NM_001347721.2:c.47G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-37472720-G-A
• chr21-37472720-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4 BP6_Moderate

The NM_001347721.2(DYRK1A):​c.47G>A​(p.Arg16Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DYRK1A NM_001347721.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.60

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DYRK1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 88 curated benign missense variants. Gene score misZ: 3.3441 (above the threshold of 3.09). Trascript score misZ: 4.1103 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, DYRK1A-related intellectual disability syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31274283).
• BP6: Variant 21-37472720-G-A is Benign according to our data. Variant chr21-37472720-G-A is described in ClinVar as [Benign]. Clinvar id is 472252.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.47G>A	p.Arg16Gln	missense_variant	Exon 3 of 12	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.47G>A	p.Arg16Gln	missense_variant	Exon 3 of 12		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456464 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 724698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DYRK1A-related intellectual disability syndrome Benign:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	.;.;T;.;.;.;.;T;T;T;.;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;.;.;D;.;D;D;.;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.0	.;L;L;L;L;L;.;.;L;L;L;L;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.42	.;.;.;.;N;.;.;N;N;N;.;.;.;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;D;D;D;.;.;.;D
Sift4G	Benign	0.37	.;.;.;.;T;.;.;T;T;T;.;.;.;T
Polyphen		0.086, 0.052	.;B;B;B;B;B;.;.;B;B;B;B;.;B
Vest4		0.63, 0.66, 0.68, 0.63
MutPred		0.15		Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);Loss of phosphorylation at S14 (P = 0.0831);.;Loss of phosphorylation at S14 (P = 0.0831);
MVP		0.73
MPC		1.7
ClinPred		0.88	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.52
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057175147; hg19: chr21-38845022;