Variant 15-65691020-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001320835.1(DENND4A):c.3574C>T(p.Arg1192Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,611,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DENND4A
NM_001320835.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

Variant links:

Genes affected

DENND4A (HGNC:24321): (DENN domain containing 4A) This gene encodes a DENN domain-containing protein that may function as a guanine nucleotide exchange factor that specifically activates ras-related protein Rab-10. This protein also contains a interferon stimulated response element-binding domain and may be involved in regulating the v-myc avian myelocytomatosis viral (MYC) oncogene. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 8. [provided by RefSeq, Mar 2016]

DENND4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06422487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND4A	NM_001320835.1 linkuse as main transcript	c.3574C>T	p.Arg1192Cys	missense_variant	23/33	ENST00000443035.8	NP_001307764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND4A	ENST00000443035.8 linkuse as main transcript	c.3574C>T	p.Arg1192Cys	missense_variant	23/33	1	NM_001320835.1	ENSP00000391167	A1
DENND4A	ENST00000431932.6 linkuse as main transcript	c.3442C>T	p.Arg1148Cys	missense_variant	22/32	1		ENSP00000396830	P3	Q7Z401-1
DENND4A	ENST00000635620.2 linkuse as main transcript	c.3571C>T	p.Arg1191Cys	missense_variant	22/33	5		ENSP00000489304	A1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

GnomAD3 exomes

AF:

0.00000816

AC:

AN:

245024

Hom.:

AF XY:

0.00000752

AC XY:

AN XY:

132926

show subpopulations

Gnomad AFR exome

AF:

0.0000664

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:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1459362

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

725752

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000452

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:

0.00000810

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000268

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000166

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

Dec 19, 2022

The c.3571C>T (p.R1191C) alteration is located in exon 23 (coding exon 21) of the DENND4A gene. This alteration results from a C to T substitution at nucleotide position 3571, causing the arginine (R) at amino acid position 1191 to be replaced by a cysteine (C). 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

0.093

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.14

.;T;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.0088

MetaRNN

Benign

0.064

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Benign

0.081

Sift

Uncertain

0.018

D;D;.

Sift4G

Uncertain

0.034

D;D;D

Polyphen

0.0040

.;B;.

Vest4

0.16

MVP

0.28

MPC

0.13

ClinPred

0.14

GERP RS

3.7

Varity_R

0.12

gMVP

0.53

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