12-112163651-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The NM_001388303.1(HECTD4):c.12788G>A(p.Arg4263Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,540,968 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00038 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
HECTD4
NM_001388303.1 missense
NM_001388303.1 missense
Scores
5
4
6
Clinical Significance
Conservation
PhyloP100: 7.39
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 Likely_benign. 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=0.024242133).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HECTD4 | NM_001388303.1 | c.12788G>A | p.Arg4263Gln | missense_variant | 74/76 | ENST00000682272.1 | NP_001375232.1 | |
HECTD4 | NM_001109662.4 | c.12818G>A | p.Arg4273Gln | missense_variant | 74/76 | NP_001103132.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HECTD4 | ENST00000682272.1 | c.12788G>A | p.Arg4263Gln | missense_variant | 74/76 | NM_001388303.1 | ENSP00000507687 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000381 AC: 58AN: 152222Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000308 AC: 44AN: 142882Hom.: 0 AF XY: 0.000275 AC XY: 21AN XY: 76424
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GnomAD4 exome AF: 0.000155 AC: 215AN: 1388628Hom.: 0 Cov.: 33 AF XY: 0.000152 AC XY: 104AN XY: 684690
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GnomAD4 genome AF: 0.000381 AC: 58AN: 152340Hom.: 1 Cov.: 32 AF XY: 0.000456 AC XY: 34AN XY: 74500
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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 | Dec 05, 2022 | The c.12272G>A (p.R4091Q) alteration is located in exon 73 (coding exon 72) of the HECTD4 gene. This alteration results from a G to A substitution at nucleotide position 12272, causing the arginine (R) at amino acid position 4091 to be replaced by a glutamine (Q). 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
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
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
Uncertain
Sift4G
Benign
T;T
Vest4
MVP
MPC
ClinPred
T
GERP RS
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