chr14-75013942-G-A
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2
The NM_001040108.2(MLH3):c.*3140C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 190,892 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.0099 ( 30 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 0 hom. )
Consequence
MLH3
NM_001040108.2 3_prime_UTR
NM_001040108.2 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.796
Genes affected
MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 14-75013942-G-A is Benign according to our data. Variant chr14-75013942-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314346.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00986 (1501/152286) while in subpopulation AFR AF= 0.0332 (1378/41548). AF 95% confidence interval is 0.0317. There are 30 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1501 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.*3140C>T | 3_prime_UTR_variant | 13/13 | ENST00000355774.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.*3140C>T | 3_prime_UTR_variant | 13/13 | 5 | NM_001040108.2 | P1 | ||
MLH3 | ENST00000380968.6 | c.*3140C>T | 3_prime_UTR_variant | 12/12 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00986 AC: 1501AN: 152168Hom.: 30 Cov.: 32
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GnomAD4 exome AF: 0.00272 AC: 105AN: 38606Hom.: 0 Cov.: 0 AF XY: 0.00262 AC XY: 47AN XY: 17946
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GnomAD4 genome AF: 0.00986 AC: 1501AN: 152286Hom.: 30 Cov.: 32 AF XY: 0.00955 AC XY: 711AN XY: 74460
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Vanishing white matter disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at