NM_003472.4:c.526G>C

Variant names:

• chr6-18255778-C-G
• rs1791569376
• NM_003472.4:c.526G>C

Variant summary

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

The NM_003472.4(DEK):​c.526G>C​(p.Val176Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DEK NM_003472.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

Genes affected

DEK (HGNC:2768): (DEK proto-oncogene) This gene encodes a protein with one SAP domain. This protein binds to cruciform and superhelical DNA and induces positive supercoils into closed circular DNA, and is also involved in splice site selection during mRNA processing. Chromosomal aberrations involving this region, increased expression of this gene, and the presence of antibodies against this protein are all associated with various diseases. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEK	NM_003472.4	c.526G>C	p.Val176Leu	missense_variant	Exon 6 of 11	ENST00000652689.1	NP_003463.1
DEK	NM_001134709.2	c.424G>C	p.Val142Leu	missense_variant	Exon 5 of 10		NP_001128181.1
DEK	XM_024446544.2	c.526G>C	p.Val176Leu	missense_variant	Exon 6 of 11		XP_024302312.1
DEK	XM_047419335.1	c.526G>C	p.Val176Leu	missense_variant	Exon 6 of 9		XP_047275291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEK	ENST00000652689.1	c.526G>C	p.Val176Leu	missense_variant	Exon 6 of 11		NM_003472.4	ENSP00000498653.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.526G>C (p.V176L) alteration is located in exon 6 (coding exon 5) of the DEK gene. This alteration results from a G to C substitution at nucleotide position 526, causing the valine (V) at amino acid position 176 to be replaced by a leucine (L). 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	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T;D
M_CAP	Benign	0.0080	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.039	D;T;T
Sift4G	Benign	0.33	T;T;.
Polyphen		0.41	B;.;.
Vest4		0.60
MutPred		0.64		Loss of methylation at K177 (P = 0.0472);.;.;
MVP		0.80
MPC		0.40
ClinPred		0.72	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12

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: rs1791569376; hg19: chr6-18256009;