3-122564516-C-A

Variant names:

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

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]

DTX3L links:

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]

PARP9 links:

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
DTX3L	NM_138287.3 link	c.90C>A	p.Phe30Leu	missense_variant	Exon 1 of 5	ENST00000296161.9	NP_612144.1
PARP9	NM_001146105.2 link	c.-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
DTX3L	ENST00000296161.9 link	c.90C>A	p.Phe30Leu	missense_variant	Exon 1 of 5	1	NM_138287.3	ENSP00000296161.4		Q8TDB6-1
PARP9	ENST00000682323.1 link	c.-361G>T		upstream_gene_variant			NM_001146105.2	ENSP00000507390.1		Q8IXQ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152214

Hom.:

Cov.:

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:

AN:

247858

Hom.:

AF XY:

0.000112

AC XY:

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:

AN:

1460170

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

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:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

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.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000280

AC:

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

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.74

T;T

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.74

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

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.

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