dbSNP rs757551222: DENND1B:p.Arg388Leu (chr1-197553099-C-A) – ACMG Classification: Uncertain_significance (4 pts)

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

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]

DENND1B links:

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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
DENND1B	NM_001195215.2 link	c.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	UniProt
DENND1B	ENST00000620048.6 link	c.1163G>T	p.Arg388Leu	missense_variant	Exon 16 of 23	5	NM_001195215.2	ENSP00000479816.1	Q6P3S1-1
DENND1B	ENST00000367396.7 link	c.1163G>T	p.Arg388Leu	missense_variant	Exon 16 of 16	1		ENSP00000356366.3	Q6P3S1-5
DENND1B	ENST00000235453.8 link	c.1073G>T	p.Arg358Leu	missense_variant	Exon 16 of 16	1		ENSP00000235453.4	Q6P3S1-4
DENND1B	ENST00000294737.11 link	n.988-6326G>T		intron_variant	Intron 13 of 19	2		ENSP00000294737.7	B3KR95

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1369976

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

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.:

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

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.9

M;.;M

PrimateAI

Uncertain

0.73

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over