Genetic Variant DYRK1B:p.Pro614Thr (chr19-39825765-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004714.3(DYRK1B):c.1840C>A(p.Pro614Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,570,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

DYRK1B
NM_004714.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.24

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

abdominal obesity-metabolic syndrome 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

DYRK1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031339288).

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1B	NM_004714.3 link	c.1840C>A	p.Pro614Thr	missense_variant	Exon 11 of 11	ENST00000323039.10	NP_004705.1	Q9Y463-1A0A024R0I0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1B	ENST00000323039.10 link	c.1840C>A	p.Pro614Thr	missense_variant	Exon 11 of 11	1	NM_004714.3	ENSP00000312789.4		Q9Y463-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000180

AC:

AN:

172096

AF XY:

0.000245

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000382

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000609

Gnomad NFE exome

AF:

0.000402

Gnomad OTH exome

AF:

0.000216

GnomAD4 exome

AF:

0.000245

AC:

348

AN:

1418334

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

181

AN XY:

701858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32374

American (AMR)

AF:

0.0000537

AC:

AN:

37236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25420

East Asian (EAS)

AF:

0.00

AC:

AN:

36928

South Asian (SAS)

AF:

0.00

AC:

AN:

81778

European-Finnish (FIN)

AF:

0.0000200

AC:

AN:

49896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5170

European-Non Finnish (NFE)

AF:

0.000308

AC:

336

AN:

1090746

Other (OTH)

AF:

0.000153

AC:

AN:

58786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000125

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41400

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.000179

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DYRK1B-related disorder

Uncertain:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DYRK1B c.1840C>A variant is predicted to result in the amino acid substitution p.Pro614Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;T;.;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

0.0044

FATHMM_MKL

Benign

0.68

M_CAP

Benign

0.013

MetaRNN

Benign

0.031

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;L;.;.;.

PhyloP100

1.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.12

.;N;N;.;N

REVEL

Benign

0.049

Sift

Uncertain

0.015

.;D;D;.;D

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.020

B;B;B;B;B

Vest4

0.18

MVP

0.51

MPC

0.56

ClinPred

0.073

GERP RS

5.0

Varity_R

0.12

gMVP

0.24

Mutation Taster

=80/20

polymorphism

(source)

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

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19-39825765-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over