4-88462281-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_016323.4(HERC5):c.613G>A(p.Ala205Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,022 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 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
HERC5
NM_016323.4 missense
NM_016323.4 missense
Scores
12
7
Clinical Significance
Conservation
PhyloP100: 4.19
Genes affected
HERC5 (HGNC:24368): (HECT and RLD domain containing E3 ubiquitin protein ligase 5) This gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and five RCC1 repeats. Pro-inflammatory cytokines upregulate expression of this gene in endothelial cells. The protein localizes to the cytoplasm and perinuclear region and functions as an interferon-induced E3 protein ligase that mediates ISGylation of protein targets. The protein also acts as a modulator of the antiviral immune response. The gene lies in a cluster of HERC family genes on chromosome 4. [provided by RefSeq, Aug 2021]
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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;
BP4
Computational evidence support a benign effect (MetaRNN=0.28448623).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HERC5 | NM_016323.4 | c.613G>A | p.Ala205Thr | missense_variant | 4/23 | ENST00000264350.8 | |
HERC5 | XM_011532022.3 | c.613G>A | p.Ala205Thr | missense_variant | 4/21 | ||
LOC102723458 | XR_938972.3 | n.19+5350C>T | intron_variant, non_coding_transcript_variant | ||||
LOC102723458 | XR_938976.3 | n.76+5350C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HERC5 | ENST00000264350.8 | c.613G>A | p.Ala205Thr | missense_variant | 4/23 | 1 | NM_016323.4 | P1 | |
HERC5 | ENST00000508695.1 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000111 AC: 28AN: 251480Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135918
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727246
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 33 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 16, 2022 | The c.613G>A (p.A205T) alteration is located in exon 4 (coding exon 4) of the HERC5 gene. This alteration results from a G to A substitution at nucleotide position 613, causing the alanine (A) at amino acid position 205 to be replaced by a threonine (T). 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
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of glycosylation at S209 (P = 0.0617);
MVP
MPC
ClinPred
T
GERP RS
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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