Variant 15-88512970-A-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001144074.3(DET1):c.1634T>A(p.Met545Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DET1
NM_001144074.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.07

Variant links:

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]

DET1 links:

ENSG00000173867 (HGNC:):

ENSG00000173867 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
DET1	NM_001144074.3 linkuse as main transcript	c.1634T>A	p.Met545Lys	missense_variant	5/5	ENST00000268148.13	NP_001137546.1	Q7L5Y6-1A0A024RC56

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DET1	ENST00000268148.13 linkuse as main transcript	c.1634T>A	p.Met545Lys	missense_variant	5/5	1	NM_001144074.3	ENSP00000268148.8		Q7L5Y6-1
ENSG00000173867	ENST00000649547.1 linkuse as main transcript	c.1634T>A	p.Met545Lys	missense_variant	6/10			ENSP00000497509.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249124

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

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:

0.00

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000125

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.1667T>A (p.M556K) 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 1667, causing the methionine (M) at amino acid position 556 to be replaced by a lysine (K). 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

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.41

.;.;.;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;.;D

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

.;.;.;L

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.3

.;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.019

.;D;D;D

Sift4G

Uncertain

0.0090

.;D;D;D

Polyphen

0.47

.;.;.;P

Vest4

0.90, 0.93

MutPred

0.54

Loss of catalytic residue at V541 (P = 0.0152);.;.;Loss of catalytic residue at V541 (P = 0.0152);

MVP

0.31

MPC

0.61

ClinPred

0.90

GERP RS

5.0

Varity_R

0.71

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over