chr16-74623998-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_018124.4(RFWD3):c.2255T>C(p.Phe752Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
Consequence
RFWD3
NM_018124.4 missense
NM_018124.4 missense
Scores
6
7
5
Clinical Significance
Conservation
PhyloP100: 7.03
Genes affected
RFWD3 (HGNC:25539): (ring finger and WD repeat domain 3) Enables MDM2/MDM4 family protein binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in several processes, including DNA metabolic process; regulation of cell cycle phase transition; and response to ionizing radiation. Located in nucleoplasm and site of DNA damage. Colocalizes with site of double-strand break. Implicated in Fanconi anemia. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.847
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RFWD3 | NM_018124.4 | c.2255T>C | p.Phe752Ser | missense_variant | 13/13 | ENST00000361070.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RFWD3 | ENST00000361070.9 | c.2255T>C | p.Phe752Ser | missense_variant | 13/13 | 1 | NM_018124.4 | P1 | |
RFWD3 | ENST00000571750.5 | c.2255T>C | p.Phe752Ser | missense_variant | 14/14 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2022 | This variant has not been reported in the literature in individuals affected with RFWD3-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 752 of the RFWD3 protein (p.Phe752Ser). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of catalytic residue at F752 (P = 0.0769);Loss of catalytic residue at F752 (P = 0.0769);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.