4-51886620-T-G

Variant names:

• chr4-51886620-T-G
• rs375328265
• NM_001040402.3:c.396T>G

Variant summary

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

The NM_001040402.3(DCUN1D4):​c.396T>G​(p.Ile132Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DCUN1D4 NM_001040402.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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 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
DCUN1D4	NM_001040402.3	c.396T>G	p.Ile132Met	missense_variant	Exon 6 of 11	ENST00000334635.10	NP_001035492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCUN1D4	ENST00000334635.10	c.396T>G	p.Ile132Met	missense_variant	Exon 6 of 11	1	NM_001040402.3	ENSP00000334625.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461668 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.396T>G (p.I132M) alteration is located in exon 6 (coding exon 6) of the DCUN1D4 gene. This alteration results from a T to G substitution at nucleotide position 396, causing the isoleucine (I) at amino acid position 132 to be replaced by a methionine (M). 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	0.44
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.013	D;T;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.86
MVP		0.66
MPC		0.58
ClinPred		0.92	D
GERP RS		2.2
Varity_R		0.58
gMVP		0.56

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: rs375328265; hg19: chr4-52752786;