Variant chr5-118848134-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_173666.4(DTWD2):c.682G>C(p.Ala228Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,652 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: 0.0000014 ( 0 hom. )

Consequence

DTWD2
NM_173666.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.35

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 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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DTWD2	NM_173666.4 linkuse as main transcript	c.682G>C	p.Ala228Pro	missense_variant	5/6	ENST00000510708.6
DTWD2	NM_001308081.2 linkuse as main transcript	c.484G>C	p.Ala162Pro	missense_variant	5/6
DTWD2	XM_011543338.4 linkuse as main transcript	c.742G>C	p.Ala248Pro	missense_variant	6/7
DTWD2	XM_011543340.3 linkuse as main transcript	c.544G>C	p.Ala182Pro	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTWD2	ENST00000510708.6 linkuse as main transcript	c.682G>C	p.Ala228Pro	missense_variant	5/6	1	NM_173666.4	P1	Q8NBA8-1
DTWD2	ENST00000304058.8 linkuse as main transcript	c.484G>C	p.Ala162Pro	missense_variant	5/6	1			Q8NBA8-2
DTWD2	ENST00000515439.7 linkuse as main transcript	c.394G>C	p.Ala132Pro	missense_variant	3/4	5
DTWD2	ENST00000506980.2 linkuse as main transcript	c.*75G>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449652

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721092

show subpopulations

Gnomad4 AFR exome

AF:

0.0000610

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.682G>C (p.A228P) alteration is located in exon 5 (coding exon 5) of the DTWD2 gene. This alteration results from a G to C substitution at nucleotide position 682, causing the alanine (A) at amino acid position 228 to be replaced by a proline (P). 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

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;D;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.25

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.95

MutPred

0.85

.;Loss of stability (P = 0.0644);.;

MVP

0.44

MPC

0.26

ClinPred

1.0

GERP RS

5.2

Varity_R

0.88

gMVP

0.85

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