6-31971001-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005510.4(DXO):c.503C>T(p.Pro168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DXO NM_005510.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

Genes affected

DXO (HGNC:2992): (decapping exoribonuclease) This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. The function of its protein product is unknown, but its ubiquitous expression and conservation in both simple and complex eukaryotes suggests that this may be a housekeeping gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1985181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DXO	NM_005510.4	c.503C>T	p.Pro168Leu	missense_variant	3/7	ENST00000337523.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DXO	ENST00000337523.10	c.503C>T	p.Pro168Leu	missense_variant	3/7	1	NM_005510.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460756 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726696

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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 04, 2023

The c.503C>T (p.P168L) alteration is located in exon 3 (coding exon 2) of the DXO gene. This alteration results from a C to T substitution at nucleotide position 503, causing the proline (P) at amino acid position 168 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	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	22
Dann	Benign	0.93
DEOGEN2	Benign	0.070	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.035	D;D;D
Sift4G	Benign	0.33	T;T;T
Polyphen		0.93	P;P;P
Vest4		0.24
MutPred		0.38		Loss of disorder (P = 0.0333);Loss of disorder (P = 0.0333);Loss of disorder (P = 0.0333);
MVP		0.47
MPC		0.39
ClinPred		0.85	D
GERP RS		4.4
Varity_R		0.069
gMVP		0.56

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

Other links and lift over

dbSNP: rs769891437; hg19: chr6-31938778;