Variant 1-153933212-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_014856.3(DENND4B):c.3438G>C(p.Gln1146His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DENND4B
NM_014856.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.191

Variant links:

Genes affected

DENND4B (HGNC:29044): (DENN domain containing 4B) Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Rab protein signal transduction. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DENND4B links:

DENND4B (HGNC:):

DENND4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DENND4B. . Gene score misZ 3.2312 (greater than the threshold 3.09). Trascript score misZ 4.0136 (greater than threshold 3.09). GenCC has associacion of gene with isolated cleft palate.

BP4

Computational evidence support a benign effect (MetaRNN=0.112486094).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND4B	NM_014856.3 linkuse as main transcript	c.3438G>C	p.Gln1146His	missense_variant	21/28	ENST00000361217.9	NP_055671.2	O75064

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND4B	ENST00000361217.9 linkuse as main transcript	c.3438G>C	p.Gln1146His	missense_variant	21/28	1	NM_014856.3	ENSP00000354597.4		O75064

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

247322

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

134150

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:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1460826

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726610

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

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 27, 2023

The c.3438G>C (p.Q1146H) alteration is located in exon 21 (coding exon 20) of the DENND4B gene. This alteration results from a G to C substitution at nucleotide position 3438, causing the glutamine (Q) at amino acid position 1146 to be replaced by a histidine (H). 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

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.041

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.019

D;.

Polyphen

0.45

P;.

Vest4

0.12

MutPred

0.13

Gain of catalytic residue at Q1146 (P = 0.0185);.;

MVP

0.14

MPC

1.7

ClinPred

0.38

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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