9-19305504-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001330640.2(DENND4C):āc.1464C>Gā(p.Asp488Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000089 ( 0 hom. )
Consequence
DENND4C
NM_001330640.2 missense
NM_001330640.2 missense
Scores
6
6
2
Clinical Significance
Conservation
PhyloP100: 2.02
Genes affected
DENND4C (HGNC:26079): (DENN domain containing 4C) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular response to insulin stimulus; protein localization to plasma membrane; and regulation of Rab protein signal transduction. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]
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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, 0.867
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DENND4C | NM_001330640.2 | c.1464C>G | p.Asp488Glu | missense_variant | 10/33 | ENST00000434457.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DENND4C | ENST00000434457.7 | c.1464C>G | p.Asp488Glu | missense_variant | 10/33 | 5 | NM_001330640.2 | P4 | |
DENND4C | ENST00000494124.2 | c.783C>G | p.Asp261Glu | missense_variant, NMD_transcript_variant | 6/28 | 1 | |||
DENND4C | ENST00000602925.5 | c.1464C>G | p.Asp488Glu | missense_variant | 10/32 | 5 | A1 | ||
DENND4C | ENST00000380437.8 | n.782C>G | non_coding_transcript_exon_variant | 6/29 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250654Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135554
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GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460660Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726682
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288
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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 | Apr 27, 2022 | The c.756C>G (p.D252E) alteration is located in exon 6 (coding exon 6) of the DENND4C gene. This alteration results from a C to G substitution at nucleotide position 756, causing the aspartic acid (D) at amino acid position 252 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
Sift4G
Pathogenic
D;D
Vest4
MVP
MPC
0.26
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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