Variant 15-65690510-C-T 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_001320835.1(DENND4A):c.4084G>A(p.Val1362Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,072 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: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

DENND4A
NM_001320835.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

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:

DENND4A (HGNC:):

DENND4A 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=0.21102625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND4A	NM_001320835.1 linkuse as main transcript	c.4084G>A	p.Val1362Ile	missense_variant	23/33	ENST00000443035.8	NP_001307764.1	A0A7I2RAZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DENND4A	ENST00000443035.8 linkuse as main transcript	c.4084G>A	p.Val1362Ile	missense_variant	23/33	1	NM_001320835.1	ENSP00000391167.4	A0A7I2RAZ6
DENND4A	ENST00000431932.6 linkuse as main transcript	c.3952G>A	p.Val1318Ile	missense_variant	22/32	1		ENSP00000396830.2	Q7Z401-1
DENND4A	ENST00000635620.2 linkuse as main transcript	c.4081G>A	p.Val1361Ile	missense_variant	22/33	5		ENSP00000489304.2	A0A0U1RR27
DENND4A	ENST00000567323.2 linkuse as main transcript	n.29G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248576

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134852

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:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461072

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726778

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.000224

Hom.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Aug 17, 2021

The c.4081G>A (p.V1361I) alteration is located in exon 23 (coding exon 21) of the DENND4A gene. This alteration results from a G to A substitution at nucleotide position 4081, causing the valine (V) at amino acid position 1361 to be replaced by an isoleucine (I). 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

0.079

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.035

.;T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.0034

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.0086

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

.;L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.47

N;N;.

REVEL

Benign

0.045

Sift

Benign

0.072

T;T;.

Sift4G

Benign

0.22

T;T;T

Polyphen

0.35

.;B;.

Vest4

0.11

MVP

0.29

MPC

0.089

ClinPred

0.11

GERP RS

3.6

Varity_R

0.043

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