rs768909607

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001352964.2(DENND1A):c.2585G>A(p.Arg862His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,502,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R862C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

DENND1A
NM_001352964.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.338

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02901104).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352964.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND1A	NM_001352964.2	MANE Select	c.2585G>A	p.Arg862His	missense	Exon 24 of 24	NP_001339893.1	A0A0A0MS48
DENND1A	NM_001393654.1		c.2531G>A	p.Arg844His	missense	Exon 23 of 23	NP_001380583.1
DENND1A	NM_001352965.2		c.2435G>A	p.Arg812His	missense	Exon 21 of 21	NP_001339894.1	Q8TEH3-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND1A	ENST00000394215.7	TSL:5 MANE Select	c.2585G>A	p.Arg862His	missense	Exon 24 of 24	ENSP00000377763.4	A0A0A0MS48
DENND1A	ENST00000473039.5	TSL:1	n.2394G>A		non_coding_transcript_exon	Exon 18 of 18
DENND1A	ENST00000866226.1		c.2531G>A	p.Arg844His	missense	Exon 23 of 23	ENSP00000536285.1

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

150714

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000145

AC:

AN:

138392

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000181

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000666

AC:

AN:

1351642

Hom.:

Cov.:

AF XY:

0.00000606

AC XY:

AN XY:

659742

show subpopulations

African (AFR)

AF:

0.000131

AC:

AN:

30584

American (AMR)

AF:

0.0000361

AC:

AN:

27718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19784

East Asian (EAS)

AF:

0.00

AC:

AN:

37780

South Asian (SAS)

AF:

0.00

AC:

AN:

68288

European-Finnish (FIN)

AF:

0.0000214

AC:

AN:

46666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5086

European-Non Finnish (NFE)

AF:

0.00000283

AC:

AN:

1059972

Other (OTH)

AF:

0.00

AC:

AN:

55764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000332

AC:

AN:

150714

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73484

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

40844

American (AMR)

AF:

0.00

AC:

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67704

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000253

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.5

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.014

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.56

M_CAP

Benign

0.0043

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.51

PhyloP100

0.34

PrimateAI

Benign

0.22

PROVEAN

Benign

0.040

REVEL

Benign

0.015

Sift

Benign

0.54

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.029

MVP

0.20

MPC

0.37

ClinPred

0.016

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.18

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over