Genetic Variant DTL:p.Thr364Met (chr1-212078228-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016448.4(DTL):c.1091C>T(p.Thr364Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,612,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DTL
NM_016448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.53

Variant links:

Genes affected

DTL (HGNC:30288): (denticleless E3 ubiquitin protein ligase homolog) Contributes to ubiquitin-protein transferase activity. Involved in several processes, including protein ubiquitination; regulation of G2/M transition of mitotic cell cycle; and translesion synthesis. Located in centrosome; cytosol; and nuclear lumen. Part of Cul4A-RING E3 ubiquitin ligase complex and Cul4B-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

DTL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTL	NM_016448.4 link	c.1091C>T	p.Thr364Met	missense_variant	Exon 12 of 15	ENST00000366991.5	NP_057532.4	Q9NZJ0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DTL	ENST00000366991.5 link	c.1091C>T	p.Thr364Met	missense_variant	Exon 12 of 15	1	NM_016448.4	ENSP00000355958.4	Q9NZJ0-1
DTL	ENST00000542077.5 link	c.965C>T	p.Thr322Met	missense_variant	Exon 11 of 14	2		ENSP00000443870.1	F5GZ90
DTL	ENST00000475419.5 link	n.906C>T		non_coding_transcript_exon_variant	Exon 10 of 13	2
DTL	ENST00000489149.1 link	n.196C>T		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

250982

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1459956

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726342

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000537

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1091C>T (p.T364M) alteration is located in exon 12 (coding exon 12) of the DTL gene. This alteration results from a C to T substitution at nucleotide position 1091, causing the threonine (T) at amino acid position 364 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Benign

-0.44

MutationAssessor

Benign

2.0

.;M

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.85

.;Gain of sheet (P = 0.1451);

MVP

0.82

MPC

1.1

ClinPred

0.59

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.70

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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