chr8-141155934-A-C

Variant names:

• chr8-141155934-A-C
• rs1302173253
• NM_001352890.3:c.1160A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001352890.3(DENND3):​c.1160A>C​(p.Asp387Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,064 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DENND3 NM_001352890.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2664129).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND3	NM_001352890.3	MANE Select	c.1160A>C	p.Asp387Ala	missense	Exon 8 of 23	NP_001339819.2	E9PF32
	DENND3	NM_001362798.2		c.1160A>C	p.Asp387Ala	missense	Exon 8 of 22	NP_001349727.1
	DENND3	NM_014957.5		c.959A>C	p.Asp320Ala	missense	Exon 8 of 23	NP_055772.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND3	ENST00000519811.6	TSL:5 MANE Select	c.1160A>C	p.Asp387Ala	missense	Exon 8 of 23	ENSP00000428714.1	E9PF32
	DENND3	ENST00000424248.2	TSL:1	c.920A>C	p.Asp307Ala	missense	Exon 7 of 21	ENSP00000410594.1	A2RUS2-2
	DENND3	ENST00000885117.1		c.1160A>C	p.Asp387Ala	missense	Exon 8 of 23	ENSP00000555176.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250330 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460064 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726202

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000674 AC: 3 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110940

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.78
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.0
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.082
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Polyphen		0.10	B
Vest4		0.45
MutPred		0.35		Loss of disorder (P = 0.1068)
MVP		0.23
MPC		1.2
ClinPred		0.33	T
GERP RS		1.2
Varity_R		0.081
gMVP		0.45
Mutation Taster		=84/16	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: rs1302173253; hg19: chr8-142166033;