Variant 8-141155934-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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. 13/21 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2664129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND3	NM_001352890.3 linkuse as main transcript	c.1160A>C	p.Asp387Ala	missense_variant	8/23	ENST00000519811.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND3	ENST00000519811.6 linkuse as main transcript	c.1160A>C	p.Asp387Ala	missense_variant	8/23	5	NM_001352890.3	P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250330

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135346

show subpopulations

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 SAS 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:

AN:

1460064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.920A>C (p.D307A) alteration is located in exon 8 (coding exon 7) of the DENND3 gene. This alteration results from a A to C substitution at nucleotide position 920, causing the aspartic acid (D) at amino acid position 307 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.16

T;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.59

T;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.2

M;.;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Benign

0.082

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.10

B;P;.

Vest4

0.45

MutPred

0.35

.;Loss of disorder (P = 0.1068);.;

MVP

0.23

MPC

1.2

ClinPred

0.33

GERP RS

1.2

Varity_R

0.081

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over