15-88530796-A-G

Position:

• chr15-88530796-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001144074.3(DET1):​c.910T>C​(p.Trp304Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DET1 NM_001144074.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.47

Genes affected

DET1 (HGNC:25477): (DET1 partner of COP1 E3 ubiquitin ligase) Enables ubiquitin ligase-substrate adaptor activity and ubiquitin protein ligase binding activity. Involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; protein ubiquitination; and protein-containing complex assembly. Part of Cul4A-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000173867 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DET1	NM_001144074.3	c.910T>C	p.Trp304Arg	missense_variant	2/5	ENST00000268148.13	NP_001137546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DET1	ENST00000268148.13	c.910T>C	p.Trp304Arg	missense_variant	2/5	1	NM_001144074.3	ENSP00000268148.8
ENSG00000173867	ENST00000649547.1	c.910T>C	p.Trp304Arg	missense_variant	3/10			ENSP00000497509.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 12, 2024

The c.943T>C (p.W315R) alteration is located in exon 3 (coding exon 2) of the DET1 gene. This alteration results from a T to C substitution at nucleotide position 943, causing the tryptophan (W) at amino acid position 315 to be replaced by an arginine (R). 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	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;.;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;.;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.2	.;.;.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	.;D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		0.93	.;.;.;P
Vest4		0.94
MutPred		0.76		Gain of disorder (P = 0.0094);.;.;Gain of disorder (P = 0.0094);
MVP		0.30
MPC		0.69
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.94
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-89074027;