chr14-75048422-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_001040108.2(MLH3):āc.1234A>Gā(p.Lys412Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,608,284 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001040108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.1234A>G | p.Lys412Glu | missense_variant | Exon 2 of 13 | 5 | NM_001040108.2 | ENSP00000348020.2 | ||
MLH3 | ENST00000380968.6 | c.1234A>G | p.Lys412Glu | missense_variant | Exon 2 of 12 | 1 | ENSP00000370355.3 | |||
MLH3 | ENST00000556257.5 | c.1234A>G | p.Lys412Glu | missense_variant | Exon 2 of 7 | 5 | ENSP00000451540.1 |
Frequencies
GnomAD3 genomes AF: 0.000578 AC: 88AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000448 AC: 110AN: 245414Hom.: 0 AF XY: 0.000452 AC XY: 60AN XY: 132634
GnomAD4 exome AF: 0.000707 AC: 1029AN: 1455942Hom.: 1 Cov.: 35 AF XY: 0.000684 AC XY: 495AN XY: 723890
GnomAD4 genome AF: 0.000578 AC: 88AN: 152342Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54AN XY: 74502
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Uncertain:1
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Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1
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MLH3-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at