Genetic Variant DTX3L:p.Pro225Ser (chr3-122568762-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_138287.3(DTX3L):c.673C>T(p.Pro225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DTX3L
NM_138287.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.287

Variant links:

Genes affected

DTX3L (HGNC:30323): (deltex E3 ubiquitin ligase 3L) Enables several functions, including STAT family protein binding activity; ubiquitin-like protein ligase binding activity; and ubiquitin-protein transferase activity. Involved in several processes, including positive regulation of macromolecule metabolic process; positive regulation of protein localization; and protein ubiquitination. Located in cytosol; lysosome; and nucleoplasm. Part of protein-containing complex. Colocalizes with early endosome and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DTX3L links:

Genome browser will be placed here

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=0.04604116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTX3L	NM_138287.3 link	c.673C>T	p.Pro225Ser	missense_variant	Exon 3 of 5	ENST00000296161.9	NP_612144.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTX3L	ENST00000296161.9 link	c.673C>T	p.Pro225Ser	missense_variant	Exon 3 of 5	1	NM_138287.3	ENSP00000296161.4		Q8TDB6-1
DTX3L	ENST00000383661.3 link	c.400-1693C>T		intron_variant	Intron 2 of 3	1		ENSP00000373157.3		Q8TDB6-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673C>T (p.P225S) alteration is located in exon 3 (coding exon 3) of the DTX3L gene. This alteration results from a C to T substitution at nucleotide position 673, causing the proline (P) at amino acid position 225 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

0.093

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

4.2

DANN

Benign

0.62

DEOGEN2

Benign

0.060

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.44

M_CAP

Benign

0.0067

MetaRNN

Benign

0.046

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.8

REVEL

Benign

0.090

Sift

Benign

0.84

Sift4G

Benign

0.63

Polyphen

0.037

Vest4

0.037

MutPred

0.17

Gain of phosphorylation at P225 (P = 0.0111);

MVP

0.30

MPC

0.12

ClinPred

0.13

GERP RS

3.7

Varity_R

0.036

gMVP

0.17

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