Variant 3-57692915-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152678.3(DENND6A):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,411,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DENND6A
NM_152678.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08254501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND6A	NM_152678.3 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/20	ENST00000311128.10	NP_689891.1	Q8IWF6
DENND6A	XM_006713019.4 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/20		XP_006713082.1
DENND6A	XR_007095649.1 linkuse as main transcript	n.163C>T		non_coding_transcript_exon_variant	1/21
DENND6A	XR_245100.2 linkuse as main transcript	n.163C>T		non_coding_transcript_exon_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND6A	ENST00000311128.10 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/20	1	NM_152678.3	ENSP00000311401.5		Q8IWF6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000607

AC:

AN:

164616

Hom.:

AF XY:

0.0000109

AC XY:

AN XY:

91870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1411138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000171

GnomAD4 genome

Cov.:

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

Apr 15, 2024

The c.104C>T (p.A35V) alteration is located in exon 1 (coding exon 1) of the DENND6A gene. This alteration results from a C to T substitution at nucleotide position 104, causing the alanine (A) at amino acid position 35 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.76

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.083

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.38

REVEL

Benign

0.040

Sift

Benign

0.30

Sift4G

Benign

0.29

Polyphen

0.0010

Vest4

0.051

MutPred

0.57

Gain of sheet (P = 0.0011);

MVP

0.093

MPC

0.41

ClinPred

0.10

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.029

gMVP

0.30

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