3-122564516-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_138287.3(DTX3L):​c.90C>A​(p.Phe30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,612,384 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 2 hom. )

Consequence

DTX3L
NM_138287.3 missense

Scores

5
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31
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]
PARP9 (HGNC:24118): (poly(ADP-ribose) polymerase family member 9) Enables several functions, including ADP-D-ribose binding activity; NAD+ ADP-ribosyltransferase activity; and STAT family protein binding activity. Involved in several processes, including positive regulation of nitrogen compound metabolic process; regulation of defense response; and regulation of gene expression. Located in several cellular components, including mitochondrion; nucleoplasm; and site of DNA damage. Part of protein-containing complex. Colocalizes with 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 -4 ACMG points.

BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DTX3LNM_138287.3 linkc.90C>A p.Phe30Leu missense_variant Exon 1 of 5 ENST00000296161.9 NP_612144.1
PARP9NM_001146105.2 linkc.-361G>T upstream_gene_variant ENST00000682323.1 NP_001139577.1 Q8IXQ6-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DTX3LENST00000296161.9 linkc.90C>A p.Phe30Leu missense_variant Exon 1 of 5 1 NM_138287.3 ENSP00000296161.4 Q8TDB6-1
PARP9ENST00000682323.1 linkc.-361G>T upstream_gene_variant NM_001146105.2 ENSP00000507390.1 Q8IXQ6-2

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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:
0.00
GnomAD3 exomes
AF:
0.000202
AC:
50
AN:
247858
Hom.:
2
AF XY:
0.000112
AC XY:
15
AN XY:
134472
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00125
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:
0.00116
GnomAD4 exome
AF:
0.0000466
AC:
68
AN:
1460170
Hom.:
2
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
726406
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00110
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:
0.0000144
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000327
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:
0.00
Alfa
AF:
0.0000368
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.000280
AC:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.90C>A (p.F30L) alteration is located in exon 1 (coding exon 1) of the DTX3L gene. This alteration results from a C to A substitution at nucleotide position 90, causing the phenylalanine (F) at amino acid position 30 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
Pathogenic
0.97
BayesDel_addAF
Benign
-0.0080
T
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.74
T;T
M_CAP
Pathogenic
0.52
D
MetaRNN
Benign
0.25
T;T
MetaSVM
Benign
-0.43
T
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.6
D;N
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.083
T;T
Polyphen
1.0
D;D
Vest4
0.68
MutPred
0.36
Loss of methylation at K25 (P = 0.103);Loss of methylation at K25 (P = 0.103);
MVP
0.76
MPC
0.60
ClinPred
0.21
T
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.80
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.99
Position offset: 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: rs200460795; hg19: chr3-122283363; API