chr4-88680124-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_014606.3(HERC3):c.2228C>T(p.Ala743Val) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,612,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00029 ( 0 hom. )
Consequence
HERC3
NM_014606.3 missense
NM_014606.3 missense
Scores
1
13
4
Clinical Significance
Conservation
PhyloP100: 6.01
Genes affected
HERC3 (HGNC:4876): (HECT and RLD domain containing E3 ubiquitin protein ligase 3) This gene encodes a member the HERC ubiquitin ligase family. The encoded protein is located in the cytosol and binds ubiquitin via a HECT domain. Mutations in this gene have been associated with colorectal and gastric carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]
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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;
PP2
?
Missense variant where missense usually causes diseases, HERC3
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HERC3 | NM_014606.3 | c.2228C>T | p.Ala743Val | missense_variant | 20/26 | ENST00000402738.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HERC3 | ENST00000402738.6 | c.2228C>T | p.Ala743Val | missense_variant | 20/26 | 1 | NM_014606.3 | P1 | |
HERC3 | ENST00000264345.7 | c.2228C>T | p.Ala743Val | missense_variant | 18/24 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152104Hom.: 0 Cov.: 33
GnomAD3 genomes
?
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152104
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GnomAD3 exomes AF: 0.0000959 AC: 24AN: 250212Hom.: 0 AF XY: 0.0000961 AC XY: 13AN XY: 135254
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GnomAD4 exome AF: 0.000289 AC: 422AN: 1460258Hom.: 0 Cov.: 30 AF XY: 0.000293 AC XY: 213AN XY: 726426
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GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152104Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74292
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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 13, 2022 | The c.2228C>T (p.A743V) alteration is located in exon 20 (coding exon 18) of the HERC3 gene. This alteration results from a C to T substitution at nucleotide position 2228, causing the alanine (A) at amino acid position 743 to be replaced by a valine (V). 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
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;D
Polyphen
P;P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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