12-57607160-G-C

Position:

• chr12-57607160-G-C

Variant summary

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

The NM_178502.4(DTX3):​c.297G>C​(p.Gln99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: DTX3 NM_178502.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

Genes affected

DTX3 (HGNC:24457): (deltex E3 ubiquitin ligase 3) DTX3 functions as an E3 ubiquitin ligase (Takeyama et al., 2003 [PubMed 12670957]).[supplied by OMIM, Nov 2009]

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=0.19506475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTX3	NM_178502.4	c.297G>C	p.Gln99His	missense_variant	5/7	ENST00000337737.8	NP_848597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTX3	ENST00000337737.8	c.297G>C	p.Gln99His	missense_variant	5/7	2	NM_178502.4	ENSP00000338050.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Mar 16, 2022

The c.297G>C (p.Q99H) alteration is located in exon 5 (coding exon 2) of the DTX3 gene. This alteration results from a G to C substitution at nucleotide position 297, causing the glutamine (Q) at amino acid position 99 to be replaced by a histidine (H). 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	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;T;T;T;.;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	.;T;.;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N;.;N;N;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.39	N;N;N;N;N;N
REVEL	Benign	0.068
Sift	Uncertain	0.018	D;D;D;D;D;D
Sift4G	Benign	0.10	.;T;.;.;T;T
Polyphen		0.70	P;.;P;P;.;.
Vest4		0.25
MutPred		0.15		Gain of catalytic residue at M103 (P = 0);.;Gain of catalytic residue at M103 (P = 0);Gain of catalytic residue at M103 (P = 0);.;.;
MVP		0.42
MPC		0.57
ClinPred		0.76	D
GERP RS		3.0
Varity_R		0.067
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1000700275; hg19: chr12-58000943;