MUTYH c.12C>A, p.Leu4=
NM_001128425.2:c.12C>A
Likely Benign
The variant c.12C>A (p.L4=) in MUTYH is absent from population databases (PM2 Moderate), has multiple in silico tools predicting no impact (BP4 Supporting), is reported as likely benign by reputable sources (BP6 Supporting), and is a synonymous change with no predicted splicing impact (BP7 Supporting). The aggregate evidence supports a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
MUTYH
Transcript
NM_001128425.2
Total Exons
16
Strand
Reverse (−)
Reference Sequence
NC_000001.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001128425.1 | RefSeq Select | 16 exons | Reverse |
Variant Details
HGVS Notation
NM_001128425.2:c.12C>A
Protein Change
L4=
Location
Exon 1
(Exon 1 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001128425.2
Genome Browser
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HGVS InputNM_001128425:c.12C>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.41
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is a synonymous variant (c.12C>A, p.L4=) with no predicted impact on splicing. Therefore, this criterion is not applied at Not Applied strength because the variant does not produce a null effect required by PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: p.L4= is a synonymous change causing no amino acid change. Therefore, this criterion is not applied at Not Applied strength because there is no amino acid change matching a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied at Not Applied strength because there is no evidence of de novo occurrence.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies have been conducted. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The evidence for this variant shows: no case-control data available. Therefore, this criterion is not applied at Not Applied strength because case-control prevalence data are not available.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: no evidence of localization in a mutational hotspot or critical domain. Therefore, this criterion is not applied at Not Applied strength because the variant is outside known hotspots or critical domains.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium." The evidence for this variant shows: variant not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls consistent with PM2.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no data on allelic phase or other variant. Therefore, this criterion is not applied at Not Applied strength because there is no evidence of trans configuration with a pathogenic variant.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants." The evidence for this variant shows: it is a synonymous variant causing no protein length change. Therefore, this criterion is not applied at Not Applied strength because the variant does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: it is synonymous (not missense). Therefore, this criterion is not applied at Not Applied strength because the variant is not a missense change.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied at Not Applied strength because there is no presumed de novo occurrence.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied at Not Applied strength because segregation data are lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not missense.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: in silico tools predict no impact (SpliceAI max 0.02, CADD 0.41). Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or clinical data provided. Therefore, this criterion is not applied at Not Applied strength because clinical specificity data are lacking.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but the evidence is not available to the laboratory to perform independent evaluation." The evidence for this variant shows: ClinVar reports likely benign, not pathogenic. Therefore, this criterion is not applied at Not Applied strength because no reputable source reports this variant as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not greater than 5%.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied at Not Applied strength because the allele frequency does not exceed thresholds.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant gene/disorder or homozygous for a recessive gene/disorder." The evidence for this variant shows: no observations in healthy individuals reported. Therefore, this criterion is not applied at Not Applied strength because there is no evidence of observation in unaffected individuals.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied at Not Applied strength because functional studies are lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation analysis has not been performed.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where primarily truncating variants are known to cause disease." The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not missense.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant." The evidence for this variant shows: no data on phase with other variants. Therefore, this criterion is not applied at Not Applied strength because phasing evidence is lacking.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a single-nucleotide synonymous change. Therefore, this criterion is not applied at Not Applied strength because the variant is not an in-frame indel.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)" The evidence for this variant shows: computational tools including CADD (0.41) and SpliceAI (max 0.02) predict no impact. Therefore, this criterion is applied at Supporting strength because multiple in silico predictions support a benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no cases reported with alternate molecular basis. Therefore, this criterion is not applied at Not Applied strength because such case data are unavailable.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar reports likely benign (2 laboratories). Therefore, this criterion is applied at Supporting strength because a reputable source has classified the variant as benign without available independent evidence.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "A synonymous (silent) variant for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved." The evidence for this variant shows: it is synonymous, SpliceAI predicts no impact (max score 0.02). Therefore, this criterion is applied at Supporting strength because the variant is synonymous with no predicted splicing or conservation impact.