Variant 15-65671830-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001320835.1(DENND4A):c.4426G>A(p.Ala1476Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000856 in 1,612,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

DENND4A
NM_001320835.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.90

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020846605).

BP6

Variant 15-65671830-C-T is Benign according to our data. Variant chr15-65671830-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3271564.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND4A	NM_001320835.1 linkuse as main transcript	c.4426G>A	p.Ala1476Thr	missense_variant	25/33	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.4426G>A	p.Ala1476Thr	missense_variant	25/33	1	NM_001320835.1	ENSP00000391167.4	A0A7I2RAZ6
DENND4A	ENST00000431932.6 linkuse as main transcript	c.4294G>A	p.Ala1432Thr	missense_variant	24/32	1		ENSP00000396830.2	Q7Z401-1
DENND4A	ENST00000635620.2 linkuse as main transcript	c.4423G>A	p.Ala1475Thr	missense_variant	24/33	5		ENSP00000489304.2	A0A0U1RR27

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

249168

Hom.:

AF XY:

0.000200

AC XY:

AN XY:

135174

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000842

AC:

123

AN:

1460410

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000271

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.5

DANN

Benign

0.17

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

.;N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

2.0

N;N;.

REVEL

Benign

0.073

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.11

MVP

0.24

MPC

0.088

ClinPred

0.014

GERP RS

5.0

Varity_R

0.015

gMVP

0.20

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