Variant 15-65668023-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001320835.1(DENND4A):c.4888A>G(p.Arg1630Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DENND4A
NM_001320835.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.569

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND4A	NM_001320835.1 linkuse as main transcript	c.4888A>G	p.Arg1630Gly	missense_variant	28/33	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.4888A>G	p.Arg1630Gly	missense_variant	28/33	1	NM_001320835.1	ENSP00000391167	A1
DENND4A	ENST00000431932.6 linkuse as main transcript	c.4756A>G	p.Arg1586Gly	missense_variant	27/32	1		ENSP00000396830	P3	Q7Z401-1
DENND4A	ENST00000635620.2 linkuse as main transcript	c.4885A>G	p.Arg1629Gly	missense_variant	27/33	5		ENSP00000489304	A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

247996

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

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:

0.00000205

AC:

AN:

1460530

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000451

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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 02, 2023

The c.4885A>G (p.R1629G) alteration is located in exon 28 (coding exon 26) of the DENND4A gene. This alteration results from a A to G substitution at nucleotide position 4885, causing the arginine (R) at amino acid position 1629 to be replaced by a glycine (G). 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

0.54

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

.;T;T

Eigen

Benign

0.083

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0097

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.9

D;D;.

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;D;.

Sift4G

Benign

0.13

T;T;T

Polyphen

0.84

.;P;.

Vest4

0.84

MutPred

0.34

.;Loss of MoRF binding (P = 0.0844);.;

MVP

0.47

MPC

0.21

ClinPred

0.91

GERP RS

3.0

Varity_R

0.29

gMVP

0.69

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