rs141861479
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000254.3(MTR):āc.1080A>Gā(p.Leu360=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,613,446 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00041 ( 0 hom., cov: 33)
Exomes š: 0.0010 ( 4 hom. )
Consequence
MTR
NM_000254.3 synonymous
NM_000254.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.232
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 -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
?
Variant 1-236831970-A-G is Benign according to our data. Variant chr1-236831970-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296559.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BP7
?
Synonymous conserved (PhyloP=0.232 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000414 (63/152348) while in subpopulation NFE AF= 0.000867 (59/68030). AF 95% confidence interval is 0.00069. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTR | NM_000254.3 | c.1080A>G | p.Leu360= | synonymous_variant | 13/33 | ENST00000366577.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTR | ENST00000366577.10 | c.1080A>G | p.Leu360= | synonymous_variant | 13/33 | 1 | NM_000254.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000414 AC: 63AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000414 AC: 104AN: 251328Hom.: 0 AF XY: 0.000398 AC XY: 54AN XY: 135826
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GnomAD4 exome AF: 0.00102 AC: 1484AN: 1461098Hom.: 4 Cov.: 30 AF XY: 0.00102 AC XY: 745AN XY: 726896
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GnomAD4 genome ? AF: 0.000414 AC: 63AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Disorders of Intracellular Cobalamin Metabolism Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 19, 2018 | 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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