chr8-141151638-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001352890.3(DENND3):​c.875C>T​(p.Thr292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

DENND3
NM_001352890.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
DENND3 (HGNC:29134): (DENN domain containing 3) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular protein catabolic process; endosome to lysosome transport; and regulation of Rab protein signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13490707).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DENND3NM_001352890.3 linkuse as main transcriptc.875C>T p.Thr292Met missense_variant 7/23 ENST00000519811.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DENND3ENST00000519811.6 linkuse as main transcriptc.875C>T p.Thr292Met missense_variant 7/235 NM_001352890.3 P2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
151976
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251404
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000328
AC:
48
AN:
1461872
Hom.:
0
Cov.:
33
AF XY:
0.0000358
AC XY:
26
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
151976
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74218
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 16, 2021The c.635C>T (p.T212M) alteration is located in exon 7 (coding exon 6) of the DENND3 gene. This alteration results from a C to T substitution at nucleotide position 635, causing the threonine (T) at amino acid position 212 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
Benign
0.063
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
16
DANN
Benign
0.92
DEOGEN2
Benign
0.027
T;.;T;.
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.42
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.87
D;D;D;D
M_CAP
Benign
0.0074
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;.;.;L
MutationTaster
Benign
0.67
N;N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.9
N;N;N;N
REVEL
Benign
0.10
Sift
Benign
0.11
T;T;T;T
Sift4G
Benign
0.10
T;T;D;T
Polyphen
0.22
B;B;.;.
Vest4
0.27
MVP
0.16
MPC
0.85
ClinPred
0.096
T
GERP RS
4.6
Varity_R
0.072
gMVP
0.37

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.

Other links and lift over

dbSNP: rs368117361; hg19: chr8-142161737; API