3-122566006-C-T

Variant summary

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

The NM_138287.3(DTX3L):​c.335C>T​(p.Pro112Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,614,004 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 0.00015 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

DTX3L
NM_138287.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.665
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]

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=0.022678077).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DTX3LNM_138287.3 linkc.335C>T p.Pro112Leu missense_variant Exon 2 of 5 ENST00000296161.9 NP_612144.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DTX3LENST00000296161.9 linkc.335C>T p.Pro112Leu missense_variant Exon 2 of 5 1 NM_138287.3 ENSP00000296161.4 Q8TDB6-1
DTX3LENST00000383661.3 linkc.335C>T p.Pro112Leu missense_variant Exon 2 of 4 1 ENSP00000373157.3 Q8TDB6-2

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152112
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000875
AC:
22
AN:
251466
Hom.:
0
AF XY:
0.0000883
AC XY:
12
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.000397
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:
0.000326
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.0000660
AC XY:
48
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.000612
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000432
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152112
Hom.:
0
Cov.:
31
AF XY:
0.000188
AC XY:
14
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.000298
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000218
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
Jun 18, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.335C>T (p.P112L) alteration is located in exon 2 (coding exon 2) of the DTX3L gene. This alteration results from a C to T substitution at nucleotide position 335, causing the proline (P) at amino acid position 112 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
Benign
0.069
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.060
DANN
Benign
0.56
DEOGEN2
Benign
0.025
T;.
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.43
T;T
M_CAP
Benign
0.0088
T
MetaRNN
Benign
0.023
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.2
N;N
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-0.79
N;N
REVEL
Benign
0.0040
Sift
Benign
0.18
T;T
Sift4G
Benign
0.45
T;T
Polyphen
0.0
B;B
Vest4
0.041
MutPred
0.17
Loss of glycosylation at S113 (P = 0.0784);Loss of glycosylation at S113 (P = 0.0784);
MVP
0.12
MPC
0.12
ClinPred
0.029
T
GERP RS
-9.6
Varity_R
0.015
gMVP
0.19

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.

Other links and lift over

dbSNP: rs754753553; hg19: chr3-122284853; API