rs145857775

Positions:

• chr21-37493131-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PP2 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.32

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 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	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	c.1039A>G	p.Thr347Ala	missense_variant	8/12		NM_001347721.2	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152188 Hom.: 2 Cov.: 32

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.: 1 AF XY: 0.00188 AC XY: 256 AN XY: 135842

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.: 5 Cov.: 34 AF XY: 0.00149 AC XY: 1084 AN XY: 726876

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.: 2 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74466

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.: 0

Bravo AF: 0.000801

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00155 AC: 188

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
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	D
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	T
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	D
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	T
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

Other links and lift over

dbSNP: rs145857775; hg19: chr21-38865433;