Variant 9-123382229-G-C 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_001352964.2(DENND1A):c.2416C>G(p.Arg806Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000613 in 1,609,164 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 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

DENND1A
NM_001352964.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.651

Variant links:

Genes affected

DENND1A (HGNC:29324): (DENN domain containing 1A) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1A, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (MIM 604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see MIM 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010 [PubMed 20154091]).[supplied by OMIM, Nov 2010]

DENND1A 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=0.026260167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND1A	NM_001352964.2 linkuse as main transcript	c.2416C>G	p.Arg806Gly	missense_variant	24/24	ENST00000394215.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND1A	ENST00000394215.7 linkuse as main transcript	c.2416C>G	p.Arg806Gly	missense_variant	24/24	5	NM_001352964.2	A2
DENND1A	ENST00000473039.5 linkuse as main transcript	n.2225C>G		non_coding_transcript_exon_variant	18/18	1
DENND1A	ENST00000373624.6 linkuse as main transcript	c.2233C>G	p.Arg745Gly	missense_variant	22/22	5		P2	Q8TEH3-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000503

AC:

120

AN:

238480

Hom.:

AF XY:

0.000513

AC XY:

AN XY:

130582

show subpopulations

Gnomad AFR exome

AF:

0.0000672

Gnomad AMR exome

AF:

0.000528

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000163

Gnomad NFE exome

AF:

0.000877

Gnomad OTH exome

AF:

0.000681

GnomAD4 exome

AF:

0.000638

AC:

929

AN:

1457032

Hom.:

Cov.:

AF XY:

0.000621

AC XY:

450

AN XY:

724902

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000539

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000261

Gnomad4 NFE exome

AF:

0.000771

Gnomad4 OTH exome

AF:

0.000481

GnomAD4 genome

AF:

0.000381

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000563

Hom.:

Bravo

AF:

0.000423

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000421

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00119

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

Jan 16, 2024

The c.2233C>G (p.R745G) alteration is located in exon 22 (coding exon 22) of the DENND1A gene. This alteration results from a C to G substitution at nucleotide position 2233, causing the arginine (R) at amino acid position 745 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

Benign

0.072

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.55

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.042

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.74

M_CAP

Benign

0.0077

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

REVEL

Benign

0.018

Sift

Uncertain

0.013

Sift4G

Benign

0.51

Polyphen

0.094

Vest4

0.12

MVP

0.16

MPC

0.58

ClinPred

0.030

GERP RS

2.8

Varity_R

0.083

gMVP

0.33

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