rs1060503069
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001040108.2(MLH3):c.1779A>T(p.Arg593Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R593K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001040108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.1779A>T | p.Arg593Ser | missense_variant | 2/13 | ENST00000355774.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.1779A>T | p.Arg593Ser | missense_variant | 2/13 | 5 | NM_001040108.2 | P1 | |
MLH3 | ENST00000380968.6 | c.1779A>T | p.Arg593Ser | missense_variant | 2/12 | 1 | |||
MLH3 | ENST00000556257.5 | c.1779A>T | p.Arg593Ser | missense_variant | 2/7 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2016 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH3-related disease. This sequence change replaces arginine with serine at codon 593 of the MLH3 protein (p.Arg593Ser). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at