Variant 12-113077963-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004416.3(DTX1):c.799G>C(p.Ala267Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000889 in 1,012,292 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00039 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

DTX1
NM_004416.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.566

Variant links:

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]

DTX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.053057343).

BS2

High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTX1	NM_004416.3 linkuse as main transcript	c.799G>C	p.Ala267Pro	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 linkuse as main transcript	c.799G>C	p.Ala267Pro	missense_variant	3/10	2	NM_004416.3	ENSP00000510707.1		Q86Y01
DTX1	ENST00000257600.3 linkuse as main transcript	c.799G>C	p.Ala267Pro	missense_variant	2/9	1		ENSP00000257600.3		Q86Y01

Frequencies

GnomAD3 genomes

AF:

0.000389

AC:

AN:

146620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

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:

0.00

Gnomad OTH

AF:

0.000986

GnomAD4 exome

AF:

0.0000381

AC:

AN:

865570

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

402862

show subpopulations

Gnomad4 AFR exome

AF:

0.00196

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:

0.0000342

GnomAD4 genome

AF:

0.000388

AC:

AN:

146722

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

AN XY:

71434

show subpopulations

Gnomad4 AFR

AF:

0.00129

Gnomad4 AMR

AF:

0.000135

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000976

Bravo

AF:

0.000446

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2023

The c.799G>C (p.A267P) alteration is located in exon 2 (coding exon 2) of the DTX1 gene. This alteration results from a G to C substitution at nucleotide position 799, causing the alanine (A) at amino acid position 267 to be replaced by a proline (P). 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

0.061

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.6

DANN

Benign

0.87

DEOGEN2

Benign

0.26

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.38

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.053

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.15

REVEL

Benign

0.021

Sift

Benign

0.13

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.10

MutPred

0.24

Gain of catalytic residue at P271 (P = 5e-04);

MVP

0.10

ClinPred

0.094

GERP RS

-1.3

Varity_R

0.069

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over