chr19-39825806-C-T

Variant names:

• chr19-39825806-C-T
• rs1442897061
• NM_004714.3:c.1799G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004714.3(DYRK1B):​c.1799G>A​(p.Arg600His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000942 in 1,591,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: DYRK1B NM_004714.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

Genes affected

DYRK1B (HGNC:3092): (dual specificity tyrosine phosphorylation regulated kinase 1B) This gene encodes a member of a family of nuclear-localized protein kinases. The encoded protein participates in the regulation of the cell cycle. Expression of this gene may be altered in tumor cells, and mutations in this gene were found to cause abdominal obesity-metabolic syndrome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090435684).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1B	NM_004714.3	c.1799G>A	p.Arg600His	missense_variant	Exon 11 of 11	ENST00000323039.10	NP_004705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1B	ENST00000323039.10	c.1799G>A	p.Arg600His	missense_variant	Exon 11 of 11	1	NM_004714.3	ENSP00000312789.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151984 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000149 AC: 3 AN: 200856 Hom.: 0 AF XY: 0.00000903 AC XY: 1 AN XY: 110762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000674

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000764 AC: 11 AN: 1439694 Hom.: 0 Cov.: 33 AF XY: 0.00000979 AC XY: 7 AN XY: 714744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0000356

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000454

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151984 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74220

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 600 of the DYRK1B protein (p.Arg600His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DYRK1B-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYRK1B protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;T;.;.;.
Eigen	Benign	-0.038
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.090	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.55	N;N;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.030	.;N;N;.;N
REVEL	Benign	0.062
Sift	Benign	0.31	.;T;T;.;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;D
Vest4		0.17
MutPred		0.27		Loss of methylation at R600 (P = 0.0087);Loss of methylation at R600 (P = 0.0087);.;.;.;
MVP		0.76
MPC		1.5
ClinPred		0.71	D
GERP RS		5.3
Varity_R		0.055
gMVP		0.14

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: rs1442897061; hg19: chr19-40316446;