6-110393339-T-C

Position:

• chr6-110393339-T-C

Variant summary

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

The NM_001372108.2(DDO):​c.462A>G​(p.Ile154Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DDO NM_001372108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.468

Genes affected

DDO (HGNC:2727): (D-aspartate oxidase) The protein encoded by this gene is a peroxisomal flavoprotein that catalyzes the oxidative deamination of D-aspartate and N-methyl D-aspartate. Flavin adenine dinucleotide or 6-hydroxyflavin adenine dinucleotide can serve as the cofactor in this reaction. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2019]

DDO (HGNC:):

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=0.19070742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDO	NM_001372108.2	c.462A>G	p.Ile154Met	missense_variant	5/5	ENST00000368924.9	NP_001359037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDO	ENST00000368924.9	c.462A>G	p.Ile154Met	missense_variant	5/5	1	NM_001372108.2	ENSP00000357920.4
DDO	ENST00000368923.8	c.285A>G	p.Ile95Met	missense_variant	4/4	2		ENSP00000357919.4
DDO	ENST00000479373.1	n.*104A>G		non_coding_transcript_exon_variant	4/4	5		ENSP00000436642.1
DDO	ENST00000479373.1	n.*104A>G		3_prime_UTR_variant	4/4	5		ENSP00000436642.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441600 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 713876

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: 0.00

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 24, 2024

The c.546A>G (p.I182M) alteration is located in exon 5 (coding exon 5) of the DDO gene. This alteration results from a A to G substitution at nucleotide position 546, causing the isoleucine (I) at amino acid position 182 to be replaced by a methionine (M). 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
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	3.7
DANN	Benign	0.74
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.78	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.50	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D;T
Sift4G	Uncertain	0.037	D;D
Polyphen		0.66	P;P
Vest4		0.30
MutPred		0.71		Gain of disorder (P = 0.0371);.;
MVP		0.42
MPC		0.059
ClinPred		0.82	D
GERP RS		-0.34
gMVP		0.43

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: rs750698363; hg19: chr6-110714542;