20-33851041-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_176812.5(CHMP4B):c.458T>C(p.Val153Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,610,858 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 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CHMP4B
NM_176812.5 missense
NM_176812.5 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 6.27
Genes affected
CHMP4B (HGNC:16171): (charged multivesicular body protein 4B) This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein (CHMP) protein family. The protein is part of the endosomal sorting complex required for transport (ESCRT) complex III (ESCRT-III), which functions in the sorting of endocytosed cell-surface receptors into multivesicular endosomes. The ESCRT machinery also functions in the final abscisson stage of cytokinesis and in the budding of enveloped viruses such as HIV-1. The three proteins of the CHMP4 subfamily interact with programmed cell death 6 interacting protein (PDCD6IP, also known as ALIX), which also functions in the ESCRT pathway. The CHMP4 proteins assemble into membrane-attached 5-nm filaments that form circular scaffolds and promote or stabilize outward budding. These polymers are proposed to help generate the luminal vesicles of multivesicular bodies. Mutations in this gene result in autosomal dominant posterior polar cataracts.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
?
In a chain Charged multivesicular body protein 4b (size 222) in uniprot entity CHM4B_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_176812.5
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.4090055).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHMP4B | NM_176812.5 | c.458T>C | p.Val153Ala | missense_variant | 3/5 | ENST00000217402.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHMP4B | ENST00000217402.3 | c.458T>C | p.Val153Ala | missense_variant | 3/5 | 1 | NM_176812.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458694Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725836
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
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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 | Feb 13, 2023 | The c.458T>C (p.V153A) alteration is located in exon 3 (coding exon 3) of the CHMP4B gene. This alteration results from a T to C substitution at nucleotide position 458, causing the valine (V) at amino acid position 153 to be replaced by an alanine (A). 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
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
D
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of catalytic residue at V153 (P = 0.06);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
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