1-11790692-C-T
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_005957.5(MTHFR):c.1959G>A(p.Thr653=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,614,138 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.0019 ( 4 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
MTHFR
NM_005957.5 synonymous
NM_005957.5 synonymous
Scores
6
Clinical Significance
Conservation
PhyloP100: -4.67
Genes affected
MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]
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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 (MetaRNN=0.0048999786).
BP6
Variant 1-11790692-C-T is Benign according to our data. Variant chr1-11790692-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 498489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.67 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00186 (283/152280) while in subpopulation AFR AF= 0.00657 (273/41550). AF 95% confidence interval is 0.00593. There are 4 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFR | NM_005957.5 | c.1959G>A | p.Thr653= | synonymous_variant | 12/12 | ENST00000376590.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFR | ENST00000376590.9 | c.1959G>A | p.Thr653= | synonymous_variant | 12/12 | 1 | NM_005957.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00183 AC: 278AN: 152162Hom.: 4 Cov.: 33
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GnomAD3 exomes AF: 0.000474 AC: 119AN: 251294Hom.: 1 AF XY: 0.000361 AC XY: 49AN XY: 135832
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GnomAD4 exome AF: 0.000244 AC: 356AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 162AN XY: 727220
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GnomAD4 genome AF: 0.00186 AC: 283AN: 152280Hom.: 4 Cov.: 33 AF XY: 0.00161 AC XY: 120AN XY: 74462
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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:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 03, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | MTHFR: BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 27, 2016 | - - |
Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 05, 2021 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
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Benign
T
MutationTaster
Benign
N;N;N;N
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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