12-4612614-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394779.1(DYRK4):c.1562T>C(p.Leu521Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYRK4 NM_001394779.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.613

Genes affected

DYRK4 (HGNC:3095): (dual specificity tyrosine phosphorylation regulated kinase 4) This gene encodes an enzyme that belongs to a conserved family of serine/threonine protein kinases. Members of this dual specificity kinase family are thought to function in the regulation of cell differentiation and proliferation, survival, and in development. Alternate splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08939266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYRK4	NM_001394779.1	c.1562T>C	p.Leu521Pro	missense_variant	14/15	ENST00000543431.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYRK4	ENST00000543431.6	c.1562T>C	p.Leu521Pro	missense_variant	14/15	5	NM_001394779.1	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.1217T>C (p.L406P) alteration is located in exon 12 (coding exon 10) of the DYRK4 gene. This alteration results from a T to C substitution at nucleotide position 1217, causing the leucine (L) at amino acid position 406 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
Dann	Benign	0.95
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.55	T;.;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	0.64	N;N;N;N
PrimateAI	Benign	0.30	T
REVEL	Benign	0.033
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0050	.;B;B
Vest4		0.10
MutPred		0.35		Gain of glycosylation at L521 (P = 0.0058);.;.;
MVP		0.19
MPC		0.32
ClinPred		0.14	T
GERP RS		1.9
Varity_R		0.098
gMVP		0.42

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: rs1945235758; hg19: chr12-4721780;