Variant 1-212035901-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016448.4(DTL):c.11A>G(p.Asn4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

DTL
NM_016448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.334

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:

DTL (HGNC:):

DTL links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009378761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTL	NM_016448.4 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	1/15	ENST00000366991.5	NP_057532.4	Q9NZJ0-1
DTL	NM_001286230.2 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	1/14		NP_001273159.2	B4E0E6
DTL	NM_001286229.2 linkuse as main transcript	c.-573A>G		5_prime_UTR_variant	1/13		NP_001273158.2	Q9NZJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DTL	ENST00000366991.5 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	1/15	1	NM_016448.4	ENSP00000355958.4	Q9NZJ0-1
DTL	ENST00000542077.5 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	1/14	2		ENSP00000443870.1	F5GZ90
DTL	ENST00000475419.5 linkuse as main transcript	n.56A>G		non_coding_transcript_exon_variant	1/13	2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251440

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000965

AC:

141

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00302

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000138

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000555

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

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

Oct 20, 2023

The c.11A>G (p.N4S) alteration is located in exon 1 (coding exon 1) of the DTL gene. This alteration results from a A to G substitution at nucleotide position 11, causing the asparagine (N) at amino acid position 4 to be replaced by a serine (S). 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

Benign

0.055

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.12

.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.0096

MetaRNN

Benign

0.0094

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.38

N;N

REVEL

Benign

0.099

Sift

Benign

0.12

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0

B;B

Vest4

0.099

MVP

0.62

MPC

0.25

ClinPred

0.013

GERP RS

0.46

Varity_R

0.073

gMVP

0.26

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