3-36993268-A-G
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The ENST00000673673.2(MLH1):c.-280A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 767,176 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 0.000076 ( 2 hom. )
Consequence
MLH1
ENST00000673673.2 5_prime_UTR
ENST00000673673.2 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.57
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000764 (47/614932) while in subpopulation SAS AF= 0.000912 (46/50436). AF 95% confidence interval is 0.000702. There are 2 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 8. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
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Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
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MLH1 | ENST00000673673.2 | c.-280A>G | 5_prime_UTR_variant | 1/18 | ENSP00000500979 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000764 AC: 47AN: 614932Hom.: 2 Cov.: 8 AF XY: 0.000116 AC XY: 37AN XY: 318386
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2019 | The c.-280A>G variant is located in the 5' untranslated region (5’ UTR) of the MLH1 gene. This variant results from an A to G substitution 280 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at