19-5785387-T-G

Position:

• chr19-5785387-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020175.3(DUS3L):​c.1876A>C​(p.Ile626Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DUS3L NM_020175.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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]

ENSG00000267157 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27490744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUS3L	NM_020175.3	c.1876A>C	p.Ile626Leu	missense_variant	12/13	ENST00000309061.12	NP_064560.2
DUS3L	NM_001161619.2	c.1150A>C	p.Ile384Leu	missense_variant	11/12		NP_001155091.1
DUS3L	XM_017027020.2	c.1834A>C	p.Ile612Leu	missense_variant	11/12		XP_016882509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUS3L	ENST00000309061.12	c.1876A>C	p.Ile626Leu	missense_variant	12/13	1	NM_020175.3	ENSP00000311977.5
ENSG00000267157	ENST00000586012.1	c.142A>C	p.Ile48Leu	missense_variant	2/3	3		ENSP00000466514.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000423 AC: 1 AN: 236202 Hom.: 0 AF XY: 0.00000777 AC XY: 1 AN XY: 128734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2022

The c.1876A>C (p.I626L) alteration is located in exon 12 (coding exon 12) of the DUS3L gene. This alteration results from a A to C substitution at nucleotide position 1876, causing the isoleucine (I) at amino acid position 626 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	0.11
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.032	.;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.28	T;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;.;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	.;N;N
REVEL	Benign	0.16
Sift	Benign	0.26	.;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.012, 0.039	.;B;B
Vest4		0.41, 0.34
MutPred		0.45		.;.;Loss of sheet (P = 0.0181);
MVP		0.22
MPC		0.44
ClinPred		0.31	T
GERP RS		3.3
Varity_R		0.22
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs956500052; hg19: chr19-5785398;