chr14-31109575-C-T
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_015382.4(HECTD1):c.6302G>A(p.Arg2101Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,874 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: 0.0000096 ( 0 hom. )
Consequence
HECTD1
NM_015382.4 missense
NM_015382.4 missense
Scores
2
5
11
Clinical Significance
Conservation
PhyloP100: 7.53
Genes affected
HECTD1 (HGNC:20157): (HECT domain E3 ubiquitin protein ligase 1) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in anatomical structure development; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; and protein K63-linked ubiquitination. Predicted to act upstream of or within several processes, including animal organ development; negative regulation of protein localization to plasma membrane; and protein autoubiquitination. [provided by Alliance of Genome Resources, Apr 2022]
AP4S1 (HGNC:575): (adaptor related protein complex 4 subunit sigma 1) This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.21875897).
BS2
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HECTD1 | NM_015382.4 | c.6302G>A | p.Arg2101Gln | missense_variant | 36/43 | ENST00000399332.6 | NP_056197.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HECTD1 | ENST00000399332.6 | c.6302G>A | p.Arg2101Gln | missense_variant | 36/43 | 5 | NM_015382.4 | ENSP00000382269.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249136Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135214
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727170
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74304
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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 19, 2023 | The c.6302G>A (p.R2101Q) alteration is located in exon 36 (coding exon 35) of the HECTD1 gene. This alteration results from a G to A substitution at nucleotide position 6302, causing the arginine (R) at amino acid position 2101 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;N
REVEL
Benign
Sift
Benign
.;T;T
Sift4G
Benign
T;T;T
Vest4
MutPred
0.43
.;Loss of MoRF binding (P = 0.0206);Loss of MoRF binding (P = 0.0206);
MVP
MPC
1.6
ClinPred
D
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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