12-4596238-C-A

Variant names:

• chr12-4596238-C-A
• rs1945016434
• NM_001394779.1:c.717C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001394779.1(DYRK4):​c.717C>A​(p.His239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYRK4 NM_001394779.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.614
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394779.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK4	NM_001394779.1	MANE Select	c.717C>A	p.His239Gln	missense	Exon 7 of 15	NP_001381708.1	A0A0A0MTH5
	DYRK4	NM_001371301.2		c.717C>A	p.His239Gln	missense	Exon 7 of 15	NP_001358230.1	Q9NR20-3
	DYRK4	NM_001394780.1		c.699C>A	p.His233Gln	missense	Exon 7 of 15	NP_001381709.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK4	ENST00000543431.6	TSL:5 MANE Select	c.717C>A	p.His239Gln	missense	Exon 7 of 15	ENSP00000439697.2	A0A0A0MTH5
	DYRK4	ENST00000540757.6	TSL:1	c.372C>A	p.His124Gln	missense	Exon 5 of 13	ENSP00000441755.1	Q9NR20-1
	DYRK4	ENST00000536157.5	TSL:1	n.727C>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.61
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.82
MutPred		0.45		Gain of catalytic residue at L237 (P = 0.0082)
MVP		0.70
MPC		0.46
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.96
gMVP		0.56
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs1945016434; hg19: chr12-4705404;