rs1802059
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_002454.3(MTRR):c.1911G>A(p.Ala637=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,613,790 control chromosomes in the GnomAD database, including 99,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.31 ( 7789 hom., cov: 32)
Exomes 𝑓: 0.35 ( 92166 hom. )
Consequence
MTRR
NM_002454.3 synonymous
NM_002454.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.55
Genes affected
MTRR (HGNC:7473): (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BP6
?
Variant 5-7897206-G-A is Benign according to our data. Variant chr5-7897206-G-A is described in ClinVar as [Benign]. Clinvar id is 138302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7897206-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-1.55 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTRR | NM_002454.3 | c.1911G>A | p.Ala637= | synonymous_variant | 14/15 | ENST00000440940.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTRR | ENST00000440940.7 | c.1911G>A | p.Ala637= | synonymous_variant | 14/15 | 1 | NM_002454.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.312 AC: 47414AN: 151894Hom.: 7774 Cov.: 32
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GnomAD3 exomes AF: 0.310 AC: 77864AN: 251334Hom.: 13076 AF XY: 0.319 AC XY: 43344AN XY: 135846
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GnomAD4 exome AF: 0.350 AC: 511732AN: 1461778Hom.: 92166 Cov.: 54 AF XY: 0.352 AC XY: 255796AN XY: 727186
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GnomAD4 genome ? AF: 0.312 AC: 47460AN: 152012Hom.: 7789 Cov.: 32 AF XY: 0.310 AC XY: 23008AN XY: 74324
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ClinVar
Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylcobalamin deficiency type cblE Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | Jun 19, 2021 | - - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2013 | 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. - |
Disorders of Intracellular Cobalamin Metabolism Benign:1
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at