chr12-112167507-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001388303.1(HECTD4):c.12344C>T(p.Thr4115Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000467 in 1,607,136 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 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
HECTD4
NM_001388303.1 missense
NM_001388303.1 missense
Scores
8
7
Clinical Significance
Conservation
PhyloP100: 3.94
Genes affected
HECTD4 (HGNC:26611): (HECT domain E3 ubiquitin protein ligase 4) Predicted to enable ubiquitin-protein transferase activity. Involved in glucose homeostasis and glucose metabolic process. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HECTD4. . Gene score misZ 6.9421 (greater than the threshold 3.09). Trascript score misZ 8.6089 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum.
BP4
Computational evidence support a benign effect (MetaRNN=0.15742168).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HECTD4 | NM_001388303.1 | c.12344C>T | p.Thr4115Ile | missense_variant | 72/76 | ENST00000682272.1 | NP_001375232.1 | |
HECTD4 | NM_001109662.4 | c.12374C>T | p.Thr4125Ile | missense_variant | 72/76 | NP_001103132.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HECTD4 | ENST00000682272.1 | c.12344C>T | p.Thr4115Ile | missense_variant | 72/76 | NM_001388303.1 | ENSP00000507687 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152248Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000164 AC: 4AN: 243642Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132280
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GnomAD4 exome AF: 0.0000302 AC: 44AN: 1454888Hom.: 0 Cov.: 31 AF XY: 0.0000291 AC XY: 21AN XY: 722860
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GnomAD4 genome AF: 0.000204 AC: 31AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74380
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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 | Jan 09, 2024 | The c.11828C>T (p.T3943I) alteration is located in exon 71 (coding exon 70) of the HECTD4 gene. This alteration results from a C to T substitution at nucleotide position 11828, causing the threonine (T) at amino acid position 3943 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
REVEL
Benign
Sift4G
Uncertain
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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