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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND3	NM_001352890.3 link	c.855+12C>T		intron_variant	Intron 6 of 22	ENST00000519811.6	NP_001339819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND3	ENST00000519811.6 link	c.855+12C>T		intron_variant	Intron 6 of 22	5	NM_001352890.3	ENSP00000428714.1		E9PF32

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 v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over