3-182961345-A-G

Position:

• chr3-182961345-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_020640.4(DCUN1D1):​c.401T>C​(p.Ile134Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000553 in 1,445,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000055 (0 hom.)
• Consequence: DCUN1D1 NM_020640.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

DCUN1D1 (HGNC:18184): (defective in cullin neddylation 1 domain containing 1) Enables cullin family protein binding activity. Involved in positive regulation of protein neddylation and regulation of protein ubiquitination. Located in cytosol and nucleoplasm. Part of ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28873888).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCUN1D1	NM_020640.4	c.401T>C	p.Ile134Thr	missense_variant	4/7	ENST00000292782.9	NP_065691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCUN1D1	ENST00000292782.9	c.401T>C	p.Ile134Thr	missense_variant	4/7	1	NM_020640.4	ENSP00000292782.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000553 AC: 8 AN: 1445476 Hom.: 0 Cov.: 28 AF XY: 0.00000417 AC XY: 3 AN XY: 718766

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: 0.0000122

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Dec 14, 2021

The c.401T>C (p.I134T) alteration is located in exon 4 (coding exon 4) of the DCUN1D1 gene. This alteration results from a T to C substitution at nucleotide position 401, causing the isoleucine (I) at amino acid position 134 to be replaced by a threonine (T). 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	0.076
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.090	T;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0092
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;T;.;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Benign	0.090
Sift	Benign	0.20	T;.;T;T
Sift4G	Benign	0.33	T;T;T;.
Polyphen		0.0010	B;.;.;.
Vest4		0.48
MutPred		0.68		Gain of disorder (P = 0.0126);.;.;.;
MVP		0.30
MPC		1.1
ClinPred		0.52	D
GERP RS		4.1
Varity_R		0.48
gMVP		0.59

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: rs1727382854; hg19: chr3-182679133;