rs1060500695
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000249.4(MLH1):c.1896+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000249.4 splice_region, intron
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1896+3G>A | splice_region_variant, intron_variant | ENST00000231790.8 | NP_000240.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1896+3G>A | splice_region_variant, intron_variant | 1 | NM_000249.4 | ENSP00000231790.3 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461716Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727180
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74264
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 09, 2021 | In summary, this is a novel intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098), but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. 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 MLH1-related disease. This sequence change falls in intron 16 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2023 | The c.1896+3G>A intronic variant results from a G to A substitution 3 nucleotides after coding exon 16 in the MLH1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at