rs769635872

Variant names:

• chr8-141144180-T-C
• rs769635872
• NM_001352890.3:c.656T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001352890.3(DENND3):​c.656T>C​(p.Phe219Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000048 (0 hom.)
• Consequence: DENND3 NM_001352890.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.49
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03699982).

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.656T>C	p.Phe219Ser	missense	Exon 5 of 23	NP_001339819.2	E9PF32
	DENND3	NM_001362798.2		c.656T>C	p.Phe219Ser	missense	Exon 5 of 22	NP_001349727.1
	DENND3	NM_014957.5		c.455T>C	p.Phe152Ser	missense	Exon 5 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.656T>C	p.Phe219Ser	missense	Exon 5 of 23	ENSP00000428714.1	E9PF32
	DENND3	ENST00000424248.2	TSL:1	c.416T>C	p.Phe139Ser	missense	Exon 4 of 21	ENSP00000410594.1	A2RUS2-2
	DENND3	ENST00000885117.1		c.656T>C	p.Phe219Ser	missense	Exon 5 of 23	ENSP00000555176.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 250860 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000709

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461430 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726998

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

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111918

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

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	0.19
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	N
PhyloP100		4.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.086
Sift	Benign	0.61	T
Sift4G	Benign	0.88	T
Polyphen		0.0050	B
Vest4		0.16
MutPred		0.47		Gain of disorder (P = 0.0015)
MVP		0.20
MPC		0.98
ClinPred		0.095	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.45
Mutation Taster		=89/11	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: rs769635872; hg19: chr8-142154279;