12-113077841-C-T

Variant names:

• chr12-113077841-C-T
• rs772328217
• NM_004416.3:c.677C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004416.3(DTX1):​c.677C>T​(p.Ala226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,189,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. A226T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: DTX1 NM_004416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09998047).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004416.3. 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
	DTX1	NM_004416.3	MANE Select	c.677C>T	p.Ala226Val	missense	Exon 3 of 10	NP_004407.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTX1	ENST00000548759.2	TSL:2 MANE Select	c.677C>T	p.Ala226Val	missense	Exon 3 of 10	ENSP00000510707.1	Q86Y01
	DTX1	ENST00000257600.3	TSL:1	c.677C>T	p.Ala226Val	missense	Exon 2 of 9	ENSP00000257600.3	Q86Y01
	DTX1	ENST00000929430.1		c.677C>T	p.Ala226Val	missense	Exon 3 of 9	ENSP00000599489.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000252 AC: 3 AN: 1189252 Hom.: 0 Cov.: 33 AF XY: 0.00000173 AC XY: 1 AN XY: 578718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23410

American (AMR) AF: 0.00 AC: 0 AN: 10294

Ashkenazi Jewish (ASJ) AF: 0.0000591 AC: 1 AN: 16914

East Asian (EAS) AF: 0.00 AC: 0 AN: 26866

South Asian (SAS) AF: 0.00 AC: 0 AN: 44412

European-Finnish (FIN) AF: 0.0000362 AC: 1 AN: 27632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3366

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 987802

Other (OTH) AF: 0.00 AC: 0 AN: 48556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.28	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.039
Sift	Benign	0.63	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.23		Gain of catalytic residue at P230 (P = 5e-04)
MVP		0.27
ClinPred		0.20	T
GERP RS		2.1
Varity_R		0.055
gMVP		0.12
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs772328217; hg19: chr12-113515646;