chr21-37493131-A-G

Position:

chr21-37493131-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PP2PP3BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 5 hom. )

Consequence

DYRK1A
NM_001347721.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 9.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYRK1A. . Gene score misZ 3.3441 (greater than the threshold 3.09). Trascript score misZ 4.1103 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, DYRK1A-related intellectual disability syndrome.

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 id is 383473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00176 (268/152306) while in subpopulation NFE AF= 0.00125 (85/68024). AF 95% confidence interval is 0.00103. There are 2 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 268 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK1A	NM_001347721.2 linkuse as main transcript	c.1039A>G	p.Thr347Ala	missense_variant	8/12	ENST00000647188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK1A	ENST00000647188.2 linkuse as main transcript	c.1039A>G	p.Thr347Ala	missense_variant	8/12		NM_001347721.2	P1	Q13627-2

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

152188

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00195

AC:

489

AN:

251372

Hom.:

AF XY:

0.00188

AC XY:

256

AN XY:

135842

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.00149

AC XY:

1084

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0124

Gnomad4 NFE exome

AF:

0.00135

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00176

AC:

268

AN:

152306

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0139

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.000801

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00155

AC:

188

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DYRK1A-related intellectual disability syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	DYRK1A: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DYRK1A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

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

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

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

MetaRNN

Benign

0.017

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.0

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

REVEL

Uncertain

0.50

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.015

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

Polyphen

0.98, 0.99, 0.99

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

Vest4

0.81, 0.85, 0.80

MVP

0.88

MPC

2.2

ClinPred

0.048

GERP RS

5.8

Varity_R

0.86

gMVP

0.91

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