Genetic Variant DENND1B:p.Gly395Glu (chr1-197553078-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001195215.2(DENND1B):c.1184G>A(p.Gly395Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000718 in 1,393,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

DENND1B
NM_001195215.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15

Publications

0 publications found

Variant links:

Genes affected

DENND1B (HGNC:28404): (DENN domain containing 1B) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1B, 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]

DENND1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195215.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND1B	NM_001195215.2	MANE Select	c.1184G>A	p.Gly395Glu	missense	Exon 16 of 23	NP_001182144.1	Q6P3S1-1
DENND1B	NM_144977.5		c.1184G>A	p.Gly395Glu	missense	Exon 16 of 16	NP_659414.2	Q6P3S1-5
DENND1B	NM_001300858.2		c.1094G>A	p.Gly365Glu	missense	Exon 16 of 16	NP_001287787.1	Q6P3S1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND1B	ENST00000620048.6	TSL:5 MANE Select	c.1184G>A	p.Gly395Glu	missense	Exon 16 of 23	ENSP00000479816.1	Q6P3S1-1
DENND1B	ENST00000367396.7	TSL:1	c.1184G>A	p.Gly395Glu	missense	Exon 16 of 16	ENSP00000356366.3	Q6P3S1-5
DENND1B	ENST00000235453.8	TSL:1	c.1094G>A	p.Gly365Glu	missense	Exon 16 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000523

AC:

AN:

191296

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000813

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1393670

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691364

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29346

American (AMR)

AF:

0.00

AC:

AN:

30058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24280

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35696

South Asian (SAS)

AF:

0.00

AC:

AN:

73432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085184

Other (OTH)

AF:

0.00

AC:

AN:

57610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Cov.:

ExAC

AF:

0.00000828

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

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.079

MutationAssessor

Uncertain

2.5

PhyloP100

6.2

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.46

Gain of solvent accessibility (P = 0.024)

MVP

0.75

MPC

0.34

ClinPred

0.96

GERP RS

5.6

Varity_R

0.67

gMVP

0.69

Mutation Taster

=29/71

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over