rs41530146
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000254.3(MTR):c.3599-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,601,734 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.011 ( 36 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 57 hom. )
Consequence
MTR
NM_000254.3 intron
NM_000254.3 intron
Scores
2
Splicing: ADA: 0.0001485
2
Clinical Significance
Conservation
PhyloP100: 0.132
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 1-236896996-C-A is Benign according to our data. Variant chr1-236896996-C-A is described in ClinVar as [Benign]. Clinvar id is 296583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1739/152296) while in subpopulation AFR AF= 0.0338 (1405/41548). AF 95% confidence interval is 0.0323. There are 36 homozygotes in gnomad4. There are 829 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 36 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MTR | NM_000254.3 | c.3599-10C>A | intron_variant | ENST00000366577.10 | NP_000245.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MTR | ENST00000366577.10 | c.3599-10C>A | intron_variant | 1 | NM_000254.3 | ENSP00000355536.5 | ||||
MTR | ENST00000366576.3 | c.2261-10C>A | intron_variant | 1 | ENSP00000355535.3 |
Frequencies
GnomAD3 genomes AF: 0.0114 AC: 1740AN: 152178Hom.: 36 Cov.: 32
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GnomAD3 exomes AF: 0.00496 AC: 1248AN: 251402Hom.: 18 AF XY: 0.00432 AC XY: 587AN XY: 135894
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GnomAD4 exome AF: 0.00273 AC: 3964AN: 1449438Hom.: 57 Cov.: 29 AF XY: 0.00260 AC XY: 1878AN XY: 722106
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GnomAD4 genome AF: 0.0114 AC: 1739AN: 152296Hom.: 36 Cov.: 32 AF XY: 0.0111 AC XY: 829AN XY: 74492
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 08, 2021 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2015 | 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. - |
Methylcobalamin deficiency type cblG Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Disorders of Intracellular Cobalamin Metabolism Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at