NM_138287.3:c.673C>T

Variant names:

• chr3-122568762-C-T
• rs1242373219
• NM_138287.3:c.673C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138287.3(DTX3L):​c.673C>T​(p.Pro225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DTX3L NM_138287.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.287
• Publications: 0 publications found

Genes affected

DTX3L (HGNC:30323): (deltex E3 ubiquitin ligase 3L) Enables several functions, including STAT family protein binding activity; ubiquitin-like protein ligase binding activity; and ubiquitin-protein transferase activity. Involved in several processes, including positive regulation of macromolecule metabolic process; positive regulation of protein localization; and protein ubiquitination. Located in cytosol; lysosome; and nucleoplasm. Part of protein-containing complex. Colocalizes with early endosome and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04604116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138287.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTX3L	NM_138287.3	MANE Select	c.673C>T	p.Pro225Ser	missense	Exon 3 of 5	NP_612144.1	Q8TDB6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTX3L	ENST00000296161.9	TSL:1 MANE Select	c.673C>T	p.Pro225Ser	missense	Exon 3 of 5	ENSP00000296161.4	Q8TDB6-1
	DTX3L	ENST00000383661.3	TSL:1	c.400-1693C>T		intron	N/A	ENSP00000373157.3	Q8TDB6-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.2
DANN	Benign	0.62
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.29
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.090
Sift	Benign	0.84	T
Sift4G	Benign	0.63	T
Polyphen		0.037	B
Vest4		0.037
MutPred		0.17		Gain of phosphorylation at P225 (P = 0.0111)
MVP		0.30
MPC		0.12
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.036
gMVP		0.17
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1242373219; hg19: chr3-122287609; COSMIC: COSV108102275; COSMIC: COSV108102275;