NM_001352890.3:c.2160delG

Variant names:

• chr8-141168409-AG-A
• rs1057519052
• NM_001352890.3:c.2160delG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001352890.3(DENND3):​c.2160delG​(p.Lys720AsnfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND3 NM_001352890.3 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0600
• Publications: 0 publications found

Genes affected

DENND3 (HGNC:29134): (DENN domain containing 3) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular protein catabolic process; endosome to lysosome transport; and regulation of Rab protein signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-141168409-AG-A is Pathogenic according to our data. Variant chr8-141168409-AG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375278.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352890.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND3	NM_001352890.3	MANE Select	c.2160delG	p.Lys720AsnfsTer15	frameshift	Exon 13 of 23	NP_001339819.2
	DENND3	NM_001362798.2		c.2160delG	p.Lys720AsnfsTer15	frameshift	Exon 13 of 22	NP_001349727.1
	DENND3	NM_014957.5		c.1959delG	p.Lys653AsnfsTer15	frameshift	Exon 13 of 23	NP_055772.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND3	ENST00000519811.6	TSL:5 MANE Select	c.2160delG	p.Lys720AsnfsTer15	frameshift	Exon 13 of 23	ENSP00000428714.1
	DENND3	ENST00000424248.2	TSL:1	c.1764delG	p.Lys588AsnfsTer15	frameshift	Exon 11 of 21	ENSP00000410594.1
	DENND3	ENST00000885117.1		c.2160delG	p.Lys720AsnfsTer15	frameshift	Exon 13 of 23	ENSP00000555176.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hirschsprung disease, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.060

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: rs1057519052; hg19: chr8-142178508;