rs772328217

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-113077841-C-A
• chr12-113077841-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004416.3(DTX1):​c.677C>A​(p.Ala226Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,339,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: DTX1 NM_004416.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09199765).
• BS2: High AC in GnomAdExome4 at 34 AD gene.

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>A	p.Ala226Glu	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>A	p.Ala226Glu	missense	Exon 3 of 10	ENSP00000510707.1	Q86Y01
	DTX1	ENST00000257600.3	TSL:1	c.677C>A	p.Ala226Glu	missense	Exon 2 of 9	ENSP00000257600.3	Q86Y01
	DTX1	ENST00000929430.1		c.677C>A	p.Ala226Glu	missense	Exon 3 of 9	ENSP00000599489.1

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149764 Hom.: 0 Cov.: 31

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000185 AC: 3 AN: 16224 AF XY: 0.000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000263

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000286 AC: 34 AN: 1189252 Hom.: 0 Cov.: 33 AF XY: 0.0000294 AC XY: 17 AN XY: 578718

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

American (AMR) AF: 0.000291 AC: 3 AN: 10294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16914

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

South Asian (SAS) AF: 0.0000450 AC: 2 AN: 44412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27632

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

European-Non Finnish (NFE) AF: 0.0000283 AC: 28 AN: 987802

Other (OTH) AF: 0.0000206 AC: 1 AN: 48556

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149764 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73096

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

African (AFR) AF: 0.00 AC: 0 AN: 41062

American (AMR) AF: 0.00 AC: 0 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67322

Other (OTH) AF: 0.00 AC: 0 AN: 2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000783 AC: 1

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	Uncertain	0.39
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.047
Sift	Benign	0.72	T
Sift4G	Benign	0.28	T
Polyphen		0.10	B
Vest4		0.17
MutPred		0.27		Gain of catalytic residue at P230 (P = 5e-04)
MVP		0.28
ClinPred		0.053	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.19
Mutation Taster		=94/6	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: rs772328217; hg19: chr12-113515646;