9-123382325-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001352964.2(DENND1A):c.2320G>A(p.Val774Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,609,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
DENND1A
NM_001352964.2 missense
NM_001352964.2 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 2.88
Genes affected
DENND1A (HGNC:29324): (DENN domain containing 1A) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1A, 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]
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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=0.10029012).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DENND1A | NM_001352964.2 | c.2320G>A | p.Val774Met | missense_variant | 24/24 | ENST00000394215.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DENND1A | ENST00000394215.7 | c.2320G>A | p.Val774Met | missense_variant | 24/24 | 5 | NM_001352964.2 | A2 | |
DENND1A | ENST00000473039.5 | n.2129G>A | non_coding_transcript_exon_variant | 18/18 | 1 | ||||
DENND1A | ENST00000373624.6 | c.2137G>A | p.Val713Met | missense_variant | 22/22 | 5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000164 AC: 4AN: 243900Hom.: 0 AF XY: 0.00000756 AC XY: 1AN XY: 132266
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GnomAD4 exome AF: 0.00000824 AC: 12AN: 1456848Hom.: 0 Cov.: 72 AF XY: 0.00000690 AC XY: 5AN XY: 724564
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74450
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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 submitter | clinical testing | Ambry Genetics | Jun 13, 2022 | The c.2137G>A (p.V713M) alteration is located in exon 22 (coding exon 22) of the DENND1A gene. This alteration results from a G to A substitution at nucleotide position 2137, causing the valine (V) at amino acid position 713 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at