12-113078051-G-T

Variant names:

• chr12-113078051-G-T
• rs1433417872
• NM_004416.3:c.887G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004416.3(DTX1):​c.887G>T​(p.Arg296Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000734 in 1,361,776 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: DTX1 NM_004416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.26

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTX1	NM_004416.3	c.887G>T	p.Arg296Leu	missense_variant	Exon 3 of 10	ENST00000548759.2	NP_004407.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTX1	ENST00000548759.2	c.887G>T	p.Arg296Leu	missense_variant	Exon 3 of 10	2	NM_004416.3	ENSP00000510707.1
DTX1	ENST00000257600.3	c.887G>T	p.Arg296Leu	missense_variant	Exon 2 of 9	1		ENSP00000257600.3

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 150976 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000743 AC: 9 AN: 1210800 Hom.: 0 Cov.: 31 AF XY: 0.00000845 AC XY: 5 AN XY: 591852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000523

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000178

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000608

Gnomad4 OTH exome AF: 0.0000206

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 150976 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73688

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

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: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.20
Sift	Benign	0.21	T
Sift4G	Benign	0.73	T
Polyphen		0.99	D
Vest4		0.47
MutPred		0.38		Gain of catalytic residue at L294 (P = 2e-04);
MVP		0.61
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.31
gMVP		0.67

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: rs1433417872; hg19: chr12-113515856;