Genetic Variant DENND1B:p.Ile244Met (chr1-197617700-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001195215.2(DENND1B):c.732A>G(p.Ile244Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 1,607,714 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

DENND1B
NM_001195215.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0620

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND1B	NM_001195215.2 link	c.732A>G	p.Ile244Met	missense_variant	Exon 11 of 23	ENST00000620048.6	NP_001182144.1	Q6P3S1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND1B	ENST00000620048.6 link	c.732A>G	p.Ile244Met	missense_variant	Exon 11 of 23	5	NM_001195215.2	ENSP00000479816.1		Q6P3S1-1

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000686

AC:

AN:

247910

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

134490

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000474

AC:

AN:

1456516

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

724688

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000397

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151198

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73792

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000662

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.732A>G (p.I244M) alteration is located in exon 11 (coding exon 11) of the DENND1B gene. This alteration results from a A to G substitution at nucleotide position 732, causing the isoleucine (I) at amino acid position 244 to be replaced by a methionine (M). 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

Pathogenic

0.64

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.4

.;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.95

P;D;D

Vest4

0.88

MutPred

0.56

Gain of catalytic residue at H243 (P = 0.1911);.;Gain of catalytic residue at H243 (P = 0.1911);

MVP

0.38

MPC

0.31

ClinPred

0.24

GERP RS

-5.0

Varity_R

0.79

gMVP

0.62

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