4-51863502-A-G

Variant names:

• chr4-51863502-A-G
• rs754240391
• NM_001040402.3:c.91A>G

Variant summary

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

The NM_001287757.2(DCUN1D4):​c.-90A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000137 in 1,458,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: DCUN1D4 NM_001287757.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51

Genes affected

DCUN1D4 (HGNC:28998): (defective in cullin neddylation 1 domain containing 4) Enables cullin family protein binding activity. Involved in positive regulation of protein neddylation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.15903816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCUN1D4	NM_001040402.3	c.91A>G	p.Lys31Glu	missense_variant	Exon 2 of 11	ENST00000334635.10	NP_001035492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCUN1D4	ENST00000334635.10	c.91A>G	p.Lys31Glu	missense_variant	Exon 2 of 11	1	NM_001040402.3	ENSP00000334625.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250142 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458484 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91A>G (p.K31E) alteration is located in exon 2 (coding exon 2) of the DCUN1D4 gene. This alteration results from a A to G substitution at nucleotide position 91, causing the lysine (K) at amino acid position 31 to be replaced by a glutamic acid (E). 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;.;.;.
Eigen	Benign	-0.093
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.71	N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.017	D;T;D;D
Polyphen		0.0050	B;B;.;.
Vest4		0.50
MutPred		0.29		Loss of methylation at K31 (P = 0.0093);Loss of methylation at K31 (P = 0.0093);.;.;
MVP		0.39
MPC		0.27
ClinPred		0.43	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.30

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: rs754240391; hg19: chr4-52729668;