15-88513029-A-T

Position:

• chr15-88513029-A-T

Variant summary

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

The NM_001144074.3(DET1):​c.1575T>A​(p.Phe525Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: DET1 NM_001144074.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20814052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DET1	NM_001144074.3	c.1575T>A	p.Phe525Leu	missense_variant	5/5	ENST00000268148.13	NP_001137546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DET1	ENST00000268148.13	c.1575T>A	p.Phe525Leu	missense_variant	5/5	1	NM_001144074.3	ENSP00000268148.8
ENSG00000173867	ENST00000649547.1	c.1575T>A	p.Phe525Leu	missense_variant	6/10			ENSP00000497509.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jan 24, 2024

The c.1608T>A (p.F536L) alteration is located in exon 6 (coding exon 5) of the DET1 gene. This alteration results from a T to A substitution at nucleotide position 1608, causing the phenylalanine (F) at amino acid position 536 to be replaced by a leucine (L). 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	0.76
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.20	.;.;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.95	.;D;.;D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;.;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.65	.;T;T;T
Sift4G	Benign	0.65	.;T;T;T
Polyphen		0.17	.;.;.;B
Vest4		0.58, 0.58
MutPred		0.43		Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);
MVP		0.28
MPC		0.38
ClinPred		0.35	T
GERP RS		-1.5
Varity_R		0.15
gMVP		0.54

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: chr15-89056260;