Genetic Variant DENND3:c.855+12C>T (chr8-141150965-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001352890.3(DENND3):c.855+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,519,972 control chromosomes in the GnomAD database, including 83,796 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7271 hom., cov: 34)

Exomes 𝑓: 0.33 ( 76525 hom. )

Consequence

DENND3
NM_001352890.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.28

Publications

14 publications found

Variant links:

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]

DENND3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DENND3	NM_001352890.3	MANE Select	c.855+12C>T	intron	N/A	NP_001339819.2	E9PF32
DENND3	NM_001362798.2		c.855+12C>T	intron	N/A	NP_001349727.1
DENND3	NM_014957.5		c.654+12C>T	intron	N/A	NP_055772.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DENND3	ENST00000519811.6	TSL:5 MANE Select	c.855+12C>T	intron	N/A	ENSP00000428714.1	E9PF32
DENND3	ENST00000424248.2	TSL:1	c.615+12C>T	intron	N/A	ENSP00000410594.1	A2RUS2-2
DENND3	ENST00000885117.1		c.855+12C>T	intron	N/A	ENSP00000555176.1

Frequencies

GnomAD3 genomes

AF:

0.305

AC:

46354

AN:

152110

Hom.:

7273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.273

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.258

Gnomad FIN

AF:

0.378

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.342

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.334

AC:

59472

AN:

178066

AF XY:

0.337

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.211

Gnomad FIN exome

AF:

0.389

Gnomad NFE exome

AF:

0.357

Gnomad OTH exome

AF:

0.361

GnomAD4 exome

AF:

0.332

AC:

454324

AN:

1367744

Hom.:

76525

Cov.:

AF XY:

0.332

AC XY:

223723

AN XY:

674826

show subpopulations

African (AFR)

AF:

0.262

AC:

7801

AN:

29800

American (AMR)

AF:

0.275

AC:

7441

AN:

27018

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

6159

AN:

21182

East Asian (EAS)

AF:

0.182

AC:

6652

AN:

36604

South Asian (SAS)

AF:

0.285

AC:

20201

AN:

70806

European-Finnish (FIN)

AF:

0.378

AC:

19151

AN:

50656

Middle Eastern (MID)

AF:

0.251

AC:

1342

AN:

5344

European-Non Finnish (NFE)

AF:

0.343

AC:

367420

AN:

1070260

Other (OTH)

AF:

0.324

AC:

18157

AN:

56074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

16164

32328

48492

64656

80820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11982

23964

35946

47928

59910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.305

AC:

46363

AN:

152228

Hom.:

7271

Cov.:

AF XY:

0.302

AC XY:

22486

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.264

AC:

10979

AN:

41560

American (AMR)

AF:

0.254

AC:

3886

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

948

AN:

3470

East Asian (EAS)

AF:

0.182

AC:

943

AN:

5178

South Asian (SAS)

AF:

0.258

AC:

1247

AN:

4824

European-Finnish (FIN)

AF:

0.378

AC:

4001

AN:

10596

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.342

AC:

23236

AN:

67990

Other (OTH)

AF:

0.297

AC:

627

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1640

3280

4921

6561

8201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

478

956

1434

1912

2390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.323

Hom.:

16585

Bravo

AF:

0.293

Asia WGS

AF:

0.243

AC:

845

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.053

(source)

DANN

Benign

0.63

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over