12-113077877-C-G

Position:

• chr12-113077877-C-G

Variant summary

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

The NM_004416.3(DTX1):​c.713C>G​(p.Pro238Arg) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DTX1 NM_004416.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.365

Genes affected

DTX1 (HGNC:3060): (deltex E3 ubiquitin ligase 1) Studies in Drosophila have identified this gene as encoding a positive regulator of the Notch-signaling pathway. The human gene encodes a protein of unknown function; however, it may play a role in basic helix-loop-helix transcription factor activity. [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=0.14629486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTX1	NM_004416.3	c.713C>G	p.Pro238Arg	missense_variant	3/10	ENST00000548759.2	NP_004407.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTX1	ENST00000548759.2	c.713C>G	p.Pro238Arg	missense_variant	3/10	2	NM_004416.3	ENSP00000510707.1
DTX1	ENST00000257600.3	c.713C>G	p.Pro238Arg	missense_variant	2/9	1		ENSP00000257600.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1149752 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 556100

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: 0.00

GnomAD4 genome Cov.: 31

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 28, 2024

The c.713C>G (p.P238R) alteration is located in exon 2 (coding exon 2) of the DTX1 gene. This alteration results from a C to G substitution at nucleotide position 713, causing the proline (P) at amino acid position 238 to be replaced by an arginine (R). 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	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.64
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.056
Sift	Benign	0.083	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.30		Gain of catalytic residue at P235 (P = 2e-04);
MVP		0.56
ClinPred		0.068	T
GERP RS		2.0
Varity_R		0.075
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-113515682;