12-4605039-C-G

Position:

• chr12-4605039-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001394779.1(DYRK4):​c.1252C>G​(p.Leu418Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYRK4 NM_001394779.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01

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]

ENSG00000272921 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYRK4	NM_001394779.1	c.1252C>G	p.Leu418Val	missense_variant	11/15	ENST00000543431.6	NP_001381708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYRK4	ENST00000543431.6	c.1252C>G	p.Leu418Val	missense_variant	11/15	5	NM_001394779.1	ENSP00000439697.2
ENSG00000272921	ENST00000536588.1	n.94C>G		non_coding_transcript_exon_variant	1/7	3		ENSP00000445121.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

May 23, 2024

The c.907C>G (p.L303V) alteration is located in exon 9 (coding exon 7) of the DYRK4 gene. This alteration results from a C to G substitution at nucleotide position 907, causing the leucine (L) at amino acid position 303 to be replaced by a valine (V). 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	0.18
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	.;T;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.97	D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.7	.;M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	.;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.95	.;P;P
Vest4		0.91
MutPred		0.56		Gain of catalytic residue at P417 (P = 0);.;.;
MVP		0.43
MPC		0.44
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-4714205;