15-88530693-T-A

Position:

• chr15-88530693-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001144074.3(DET1):​c.1013A>T​(p.Asp338Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DET1 NM_001144074.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DET1	NM_001144074.3	c.1013A>T	p.Asp338Val	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.1013A>T	p.Asp338Val	missense_variant	2/5	1	NM_001144074.3	ENSP00000268148.8
ENSG00000173867	ENST00000649547.1	c.1013A>T	p.Asp338Val	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

Oct 27, 2021

The c.1046A>T (p.D349V) alteration is located in exon 3 (coding exon 2) of the DET1 gene. This alteration results from a A to T substitution at nucleotide position 1046, causing the aspartic acid (D) at amino acid position 349 to be replaced by a valine (V). 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	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;.;.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.8	.;.;.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.6	.;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.99, 0.98
MutPred		0.90		Gain of helix (P = 0.0225);.;.;Gain of helix (P = 0.0225);
MVP		0.23
MPC		1.1
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.87
gMVP		0.83

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: chr15-89073924;