chr1-236824212-C-T
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000254.3(MTR):c.858C>T(p.Pro286=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,612,330 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0054 ( 5 hom., cov: 31)
Exomes 𝑓: 0.0057 ( 56 hom. )
Consequence
MTR
NM_000254.3 synonymous
NM_000254.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0530
Genes affected
MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
Variant 1-236824212-C-T is Benign according to our data. Variant chr1-236824212-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 199000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236824212-C-T is described in Lovd as [Benign]. Variant chr1-236824212-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.053 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00541 (823/152112) while in subpopulation NFE AF= 0.00693 (471/67988). AF 95% confidence interval is 0.00641. There are 5 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTR | NM_000254.3 | c.858C>T | p.Pro286= | synonymous_variant | 9/33 | ENST00000366577.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTR | ENST00000366577.10 | c.858C>T | p.Pro286= | synonymous_variant | 9/33 | 1 | NM_000254.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00541 AC: 823AN: 151994Hom.: 5 Cov.: 31
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GnomAD3 exomes AF: 0.00596 AC: 1499AN: 251448Hom.: 14 AF XY: 0.00584 AC XY: 794AN XY: 135910
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GnomAD4 exome AF: 0.00571 AC: 8336AN: 1460218Hom.: 56 Cov.: 30 AF XY: 0.00570 AC XY: 4145AN XY: 726566
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GnomAD4 genome AF: 0.00541 AC: 823AN: 152112Hom.: 5 Cov.: 31 AF XY: 0.00613 AC XY: 456AN XY: 74352
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 19, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | MTR: BP4, BP7, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 27, 2019 | - - |
Methylcobalamin deficiency type cblG Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Disorders of Intracellular Cobalamin Metabolism 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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