Variant 5-118939275-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_173666.4(DTWD2):c.325C>T(p.Arg109Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,426,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DTWD2
NM_173666.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.08

Variant links:

Genes affected

DTWD2 (HGNC:19334): (DTW domain containing 2) Enables tRNA-uridine aminocarboxypropyltransferase activity. Involved in tRNA modification. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DTWD2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTWD2	NM_173666.4 linkuse as main transcript	c.325C>T	p.Arg109Cys	missense_variant	3/6	ENST00000510708.6	NP_775937.1	Q8NBA8-1
DTWD2	NM_001308081.2 linkuse as main transcript	c.127C>T	p.Arg43Cys	missense_variant	3/6		NP_001295010.1	Q8NBA8-2
DTWD2	XM_011543338.4 linkuse as main transcript	c.325C>T	p.Arg109Cys	missense_variant	3/7		XP_011541640.3
DTWD2	XM_011543340.3 linkuse as main transcript	c.127C>T	p.Arg43Cys	missense_variant	3/7		XP_011541642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DTWD2	ENST00000510708.6 linkuse as main transcript	c.325C>T	p.Arg109Cys	missense_variant	3/6	1	NM_173666.4	ENSP00000425048.1	Q8NBA8-1
DTWD2	ENST00000304058.8 linkuse as main transcript	c.127C>T	p.Arg43Cys	missense_variant	3/6	1		ENSP00000302892.4	Q8NBA8-2
DTWD2	ENST00000515439.7 linkuse as main transcript	c.309+5284C>T		intron_variant		5		ENSP00000424221.2	D6RBD8
DTWD2	ENST00000506980.2 linkuse as main transcript	n.325C>T		non_coding_transcript_exon_variant	3/5	5		ENSP00000425016.1	D6REE2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000439

AC:

AN:

227672

Hom.:

AF XY:

0.00000809

AC XY:

AN XY:

123538

show subpopulations

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:

0.00000938

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000168

AC:

AN:

1426362

Hom.:

Cov.:

AF XY:

0.0000240

AC XY:

AN XY:

709178

show subpopulations

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:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000201

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.325C>T (p.R109C) alteration is located in exon 3 (coding exon 3) of the DTWD2 gene. This alteration results from a C to T substitution at nucleotide position 325, causing the arginine (R) at amino acid position 109 to be replaced by a cysteine (C). 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

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.0041

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

-0.099

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

.;D

Vest4

0.90

MutPred

0.68

.;Loss of solvent accessibility (P = 0.0079);

MVP

0.43

MPC

0.26

ClinPred

1.0

GERP RS

5.8

Varity_R

0.61

gMVP

0.70

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.

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