Genetic Variant DUS3L:p.Trp528Arg (chr19-5785772-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020175.3(DUS3L):c.1582T>C(p.Trp528Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DUS3L
NM_020175.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.83

Variant links:

Genes affected

DUS3L (HGNC:26920): (dihydrouridine synthase 3 like) Enables RNA binding activity. Predicted to be involved in tRNA dihydrouridine synthesis. [provided by Alliance of Genome Resources, Apr 2022]

DUS3L links:

ENSG00000267157 (HGNC:):

ENSG00000267157 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUS3L	NM_020175.3 link	c.1582T>C	p.Trp528Arg	missense_variant	Exon 11 of 13	ENST00000309061.12	NP_064560.2	Q96G46-1B2RDV7
DUS3L	NM_001161619.2 link	c.856T>C	p.Trp286Arg	missense_variant	Exon 10 of 12		NP_001155091.1	Q96G46-3
DUS3L	XM_017027020.2 link	c.1540T>C	p.Trp514Arg	missense_variant	Exon 10 of 12		XP_016882509.1
DUS3L	XM_047439111.1 link	c.*27T>C		3_prime_UTR_variant	Exon 10 of 10		XP_047295067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUS3L	ENST00000309061.12 link	c.1582T>C	p.Trp528Arg	missense_variant	Exon 11 of 13	1	NM_020175.3	ENSP00000311977.5		Q96G46-1
ENSG00000267157	ENST00000586012.1 link	c.-153T>C		upstream_gene_variant		3		ENSP00000466514.1		K7EMI3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722322

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1582T>C (p.W528R) alteration is located in exon 11 (coding exon 11) of the DUS3L gene. This alteration results from a T to C substitution at nucleotide position 1582, causing the tryptophan (W) at amino acid position 528 to be replaced by an arginine (R). 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

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Pathogenic

4.2

.;H

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-13

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.86

.;Gain of MoRF binding (P = 0.0439);

MVP

0.70

MPC

1.7

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.98

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over