rs41283145
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002454.3(MTRR):āc.1468A>Gā(p.Thr490Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00444 in 1,614,222 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0039 ( 2 hom., cov: 33)
Exomes š: 0.0045 ( 22 hom. )
Consequence
MTRR
NM_002454.3 missense
NM_002454.3 missense
Scores
7
6
4
Clinical Significance
Conservation
PhyloP100: 7.06
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.01696533).
BP6
?
Variant 5-7892824-A-G is Benign according to our data. Variant chr5-7892824-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 439918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7892824-A-G is described in Lovd as [Likely_benign]. Variant chr5-7892824-A-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00389 (592/152336) while in subpopulation NFE AF= 0.00475 (323/68024). AF 95% confidence interval is 0.00432. There are 2 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTRR | NM_002454.3 | c.1468A>G | p.Thr490Ala | missense_variant | 11/15 | ENST00000440940.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTRR | ENST00000440940.7 | c.1468A>G | p.Thr490Ala | missense_variant | 11/15 | 1 | NM_002454.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00389 AC: 592AN: 152218Hom.: 2 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00448 AC: 1126AN: 251462Hom.: 4 AF XY: 0.00445 AC XY: 605AN XY: 135898
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GnomAD4 exome AF: 0.00450 AC: 6572AN: 1461886Hom.: 22 Cov.: 31 AF XY: 0.00428 AC XY: 3112AN XY: 727242
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GnomAD4 genome ? AF: 0.00389 AC: 592AN: 152336Hom.: 2 Cov.: 33 AF XY: 0.00469 AC XY: 349AN XY: 74482
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ESP6500AA
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | MTRR: BP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 06, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Disorders of Intracellular Cobalamin Metabolism Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Methylcobalamin deficiency type cblE Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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