14-31106812-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_015382.4(HECTD1):c.7060C>T(p.Pro2354Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,818 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 (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
HECTD1
NM_015382.4 missense
NM_015382.4 missense
Scores
7
6
5
Clinical Significance
Conservation
PhyloP100: 9.60
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.772
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HECTD1 | NM_015382.4 | c.7060C>T | p.Pro2354Ser | missense_variant | 38/43 | ENST00000399332.6 | NP_056197.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HECTD1 | ENST00000399332.6 | c.7060C>T | p.Pro2354Ser | missense_variant | 38/43 | 5 | NM_015382.4 | ENSP00000382269.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249248Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135246
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461818Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727200
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GnomAD4 genome Cov.: 32
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32
ExAC
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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 | May 18, 2023 | The c.7060C>T (p.P2354S) alteration is located in exon 38 (coding exon 37) of the HECTD1 gene. This alteration results from a C to T substitution at nucleotide position 7060, causing the proline (P) at amino acid position 2354 to be replaced by a serine (S). 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
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
.;D;D
REVEL
Uncertain
Sift
Benign
.;D;D
Sift4G
Uncertain
D;D;D
Vest4
MutPred
0.74
.;Gain of catalytic residue at N2353 (P = 0);Gain of catalytic residue at N2353 (P = 0);
MVP
MPC
0.61
ClinPred
D
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