rs34172797
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_002454.3(MTRR):c.1536C>T(p.Ser512=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,614,144 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.018 ( 34 hom., cov: 33)
Exomes 𝑓: 0.020 ( 332 hom. )
Consequence
MTRR
NM_002454.3 synonymous
NM_002454.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.367
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=-0.71).
BP6
?
Variant 5-7892892-C-T is Benign according to our data. Variant chr5-7892892-C-T is described in ClinVar as [Benign]. Clinvar id is 138297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7892892-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.367 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2674/152314) while in subpopulation NFE AF= 0.0253 (1720/68024). AF 95% confidence interval is 0.0243. There are 34 homozygotes in gnomad4. There are 1261 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 34 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTRR | NM_002454.3 | c.1536C>T | p.Ser512= | synonymous_variant | 11/15 | ENST00000440940.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTRR | ENST00000440940.7 | c.1536C>T | p.Ser512= | synonymous_variant | 11/15 | 1 | NM_002454.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0176 AC: 2672AN: 152196Hom.: 34 Cov.: 33
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GnomAD3 exomes AF: 0.0157 AC: 3949AN: 251208Hom.: 30 AF XY: 0.0153 AC XY: 2074AN XY: 135756
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GnomAD4 exome AF: 0.0205 AC: 29913AN: 1461830Hom.: 332 Cov.: 31 AF XY: 0.0200 AC XY: 14515AN XY: 727206
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GnomAD4 genome ? AF: 0.0176 AC: 2674AN: 152314Hom.: 34 Cov.: 33 AF XY: 0.0169 AC XY: 1261AN XY: 74488
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylcobalamin deficiency type cblE Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2014 | 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. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 13, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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