5-118944566-G-A

Position:

• chr5-118944566-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_173666.4(DTWD2):​c.302C>T​(p.Pro101Leu) 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: 32)
• Consequence: DTWD2 NM_173666.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.18

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]

ACMG classification

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, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTWD2	NM_173666.4	c.302C>T	p.Pro101Leu	missense_variant	2/6	ENST00000510708.6
DTWD2	NM_001308081.2	c.104C>T	p.Pro35Leu	missense_variant	2/6
DTWD2	XM_011543338.4	c.302C>T	p.Pro101Leu	missense_variant	2/7
DTWD2	XM_011543340.3	c.104C>T	p.Pro35Leu	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTWD2	ENST00000510708.6	c.302C>T	p.Pro101Leu	missense_variant	2/6	1	NM_173666.4	P1
DTWD2	ENST00000304058.8	c.104C>T	p.Pro35Leu	missense_variant	2/6	1
DTWD2	ENST00000515439.7	c.302C>T	p.Pro101Leu	missense_variant	2/4	5
DTWD2	ENST00000506980.2	c.302C>T	p.Pro101Leu	missense_variant, NMD_transcript_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

May 08, 2023

The c.302C>T (p.P101L) alteration is located in exon 2 (coding exon 2) of the DTWD2 gene. This alteration results from a C to T substitution at nucleotide position 302, causing the proline (P) at amino acid position 101 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	0.90
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;D;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.21	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.8	D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;T
Sift4G	Pathogenic	0.0	D;D;T
Polyphen		1.0	.;D;.
Vest4		0.93
MutPred		0.80		.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.71
MPC		0.24
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-118280261;