rs367643250

Positions:

chr19-39830443-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3PP5_ModerateBS2

The NM_004714.3(DYRK1B):c.304C>T(p.Arg102Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DYRK1B
NM_004714.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.72

Variant links:

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]

DYRK1B links:

ENSG00000291312 (HGNC:):

ENSG00000291312 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

PP5

Variant 19-39830443-G-A is Pathogenic according to our data. Variant chr19-39830443-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 132792.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-39830443-G-A is described in UniProt as null. Variant chr19-39830443-G-A is described in UniProt as null.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYRK1B	NM_004714.3 linkuse as main transcript	c.304C>T	p.Arg102Cys	missense_variant	4/11	ENST00000323039.10	NP_004705.1	Q9Y463-1A0A024R0I0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYRK1B	ENST00000323039.10 linkuse as main transcript	c.304C>T	p.Arg102Cys	missense_variant	4/11	1	NM_004714.3	ENSP00000312789.4		Q9Y463-1
ENSG00000291312	ENST00000706940.1 linkuse as main transcript	c.*39C>T		downstream_gene_variant				ENSP00000516660.1		A0A9L9PY30

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251468

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Abdominal obesity-metabolic syndrome 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2014

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DYRK1B function (PMID: 24827035). 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. ClinVar contains an entry for this variant (Variation ID: 132792). This missense change has been observed in individual(s) with clinical features of abdominal obesity-metabolic syndrome 3 (PMID: 24827035). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs367643250, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 102 of the DYRK1B protein (p.Arg102Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;.;.;.;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L;L;L;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.6

.;D;D;.;D;.;.

REVEL

Pathogenic

0.69

Sift

Benign

0.11

.;T;T;.;T;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;.;D

Polyphen

1.0

D;D;D;D;D;.;.

Vest4

0.90

MVP

0.56

MPC

1.3

ClinPred

0.97

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over