Variant chr3-57657707-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152678.3(DENND6A):c.791C>G(p.Pro264Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000698 in 1,575,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

DENND6A
NM_152678.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.54

Variant links:

Genes affected

DENND6A (HGNC:26635): (DENN domain containing 6A) Enables guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell-cell adhesion mediated by cadherin. Located in recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

DENND6A links:

DENND6A (HGNC:):

DENND6A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND6A	NM_152678.3 linkuse as main transcript	c.791C>G	p.Pro264Arg	missense_variant	9/20	ENST00000311128.10	NP_689891.1	Q8IWF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DENND6A	ENST00000311128.10 linkuse as main transcript	c.791C>G	p.Pro264Arg	missense_variant	9/20	1	NM_152678.3	ENSP00000311401.5	Q8IWF6
DENND6A	ENST00000477344.1 linkuse as main transcript	c.95C>G	p.Pro32Arg	missense_variant	2/6	3		ENSP00000419334.1	H7C598
DENND6A	ENST00000487662.1 linkuse as main transcript	n.431C>G		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151438

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00000420

AC:

AN:

237814

Hom.:

AF XY:

0.00000775

AC XY:

AN XY:

129054

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000321

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:

0.00000422

AC:

AN:

1423488

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

708354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000728

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:

0.00000276

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151556

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74038

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000475

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

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

Nov 27, 2023

The c.791C>G (p.P264R) alteration is located in exon 9 (coding exon 9) of the DENND6A gene. This alteration results from a C to G substitution at nucleotide position 791, causing the proline (P) at amino acid position 264 to be replaced by an arginine (R). 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

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0061

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.49

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0070

Polyphen

0.98

Vest4

0.86

MutPred

0.71

Gain of sheet (P = 0.0221);

MVP

0.42

MPC

1.3

ClinPred

0.88

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.81

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