rs757551222

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001195215.2(DENND1B):​c.1163G>T​(p.Arg388Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000146 in 1,369,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

DENND1B
NM_001195215.2 missense

Scores

12
5
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DENND1BNM_001195215.2 linkc.1163G>T p.Arg388Leu missense_variant Exon 16 of 23 ENST00000620048.6 NP_001182144.1 Q6P3S1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DENND1BENST00000620048.6 linkc.1163G>T p.Arg388Leu missense_variant Exon 16 of 23 5 NM_001195215.2 ENSP00000479816.1 Q6P3S1-1
DENND1BENST00000367396.7 linkc.1163G>T p.Arg388Leu missense_variant Exon 16 of 16 1 ENSP00000356366.3 Q6P3S1-5
DENND1BENST00000235453.8 linkc.1073G>T p.Arg358Leu missense_variant Exon 16 of 16 1 ENSP00000235453.4 Q6P3S1-4
DENND1BENST00000294737.11 linkn.988-6326G>T intron_variant Intron 13 of 19 2 ENSP00000294737.7 B3KR95

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000146
AC:
2
AN:
1369976
Hom.:
0
Cov.:
31
AF XY:
0.00000147
AC XY:
1
AN XY:
678372
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000143
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.31e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
30
DANN
Uncertain
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Uncertain
0.45
D
MutationAssessor
Uncertain
2.9
M;.;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-6.4
.;D;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.96
MutPred
0.79
Gain of ubiquitination at K391 (P = 0.0414);.;Gain of ubiquitination at K391 (P = 0.0414);
MVP
0.79
MPC
0.34
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.78
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-197522229; API