NM_001128425.2:c.690+12G>T

MUTYH · NP_001121897.1:p.? · NM_001128425.2

GRCh37: chr1:45798234 C>A · GRCh38: chr1:45332562 C>A

Gene: MUTYH Transcript: NM_001128425.2

Final call

Likely Benign

BP4 supporting BP6 supporting BP7 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.?

gnomAD AF

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

Multiple lines of computational evidence (SpliceAI max delta = 0.00) predict no splicing impact for this intronic variant at position +12 of intron 8, satisfying BP4 (supporting benign).

This intronic variant is outside the conserved splice consensus region, and splicing prediction algorithms uniformly predict no splice alteration, satisfying BP7 (supporting benign).

This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (GeneDx, VariationID: 386695), satisfying BP6 (supporting benign).

Three supporting benign criteria (BP4, BP6, BP7) are met. Under generic ACMG/AMP 2015 classification rules, this is sufficient for a Likely benign classification (u22652 supporting benign criteria).

No pathogenic criteria are met. PVS1 is not met (intronic variant outside canonical splice consensus, no predicted splice effect). PS3 is not met (no functional data). PP3 is not met (SpliceAI predicts no effect). PM2 could not be reliably assessed due to uncertain gnomAD coverage of this intronic position.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	NM_001128425.2:c.690+12G>T is an intronic variant at position +12 of intron 8, outside the canonical splice consensus (u00b11,2). The variant does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical splice site). SpliceAI predicts no significant splice impact (max delta score = 0.00). PVS1 is not applicable for this variant class.	spliceai pvs1_generic_framework
PS1	N/A	PS1 requires a different nucleotide change producing the same amino acid change as a known pathogenic variant. This is an intronic variant that does not alter the protein sequence.
PS2	Not met	No de novo observation has been reported for NM_001128425.2:c.690+12G>T in the available evidence. No publications identified for this variant.
PS3	Not met	No functional studies have been performed on NM_001128425.2:c.690+12G>T. No publications were identified for this variant. SpliceAI predicts no splicing impact (max delta = 0.00), which does not support a pathogenic functional effect.	spliceai
PS4	Not met	No case-control studies or prevalence data comparing affected versus unaffected individuals are available for NM_001128425.2:c.690+12G>T.
PS5	Not met	ClinVar classifies this variant as Likely benign (single submitter, GeneDx), not as pathogenic. There is no established reputable source reporting this variant as pathogenic.	clinvar
PM1	Not met	This is an intronic variant at position +12 of intron 8, outside any critical or well-established functional domain. No splice-region hotspot or functionally characterized domain encompasses this position.
PM2	Not assessed	gnomAD data for this intronic position could not be reliably assessed. gnomAD v2.1 (exomes only) does not cover intronic regions. gnomAD v4.1 and gnomAD-Canada returned null allele counts, indicating data extraction failure or incomplete coverage rather than confirmed absence. PM2 cannot be reliably applied without validated population frequency data for this intronic position.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 requires observation of the variant in trans with a pathogenic variant in a recessive disorder. This variant was not observed in trans with any pathogenic MUTYH variant in the available evidence, and no proband genotype data were provided.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This is a single nucleotide substitution in an intron, not a protein-length-altering variant.
PM5	N/A	PM5 requires a different missense change at the same amino acid residue as a known pathogenic variant. This is an intronic variant that does not alter any amino acid residue.
PM6	Not met	No de novo observation has been reported for NM_001128425.2:c.690+12G>T in the available evidence. No publications identified for this variant.
PP1	Not met	No cosegregation data are available for NM_001128425.2:c.690+12G>T in affected families.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common mechanism of disease and benign missense variation is rare. This is an intronic variant, not a missense change.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.00). REVEL and BayesDel are not available for this intronic variant. There is no in silico evidence supporting pathogenicity.	spliceai
PP4	Not met	No patient phenotype data are available for this variant. PP4 requires the variant to be identified in an individual with a phenotype highly specific for the gene/disease.
PP5	Not met	ClinVar classifies this variant as Likely benign (single submitter, GeneDx), not as pathogenic. There is no reputable source report of pathogenicity.	clinvar
BA1	Not met	This variant is not observed at an allele frequency >1% in any population database. gnomAD data for this intronic position is inconclusive but does not demonstrate a frequency consistent with BA1.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is not observed at an allele frequency >0.3% in any population database. gnomAD data for this intronic position is inconclusive but does not demonstrate a frequency consistent with BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No data available for observation of this variant in healthy adult individuals. MUTYH-associated polyposis follows autosomal recessive inheritance, which limits the applicability of BS2 anyway.
BS3	Not met	No well-established functional studies have been performed on NM_001128425.2:c.690+12G>T that show no damaging effect. While SpliceAI predicts no splicing impact, this is computational evidence (BP4/BP7 territory) rather than well-established functional data.	spliceai
BS4	Not met	No cosegregation data are available to demonstrate lack of segregation with disease for NM_001128425.2:c.690+12G>T.
BP1	N/A	BP1 applies to missense variants in genes where a truncating mechanism is primarily known to cause disease. This is an intronic variant, not a missense change.
BP2	Not met	BP2 requires observation in trans with a pathogenic variant in a fully penetrant dominant disorder. MUTYH-associated polyposis is an autosomal recessive disorder, and no trans data are available for this variant.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions. This is a single nucleotide substitution, not an in-frame indel.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product or splicing. SpliceAI predicts no significant splice alteration (max delta score = 0.00). REVEL and BayesDel could not be assessed for this intronic variant, but the available evidence uniformly indicates a benign computational profile.	spliceai
BP5	Not met	No evidence that this variant has been observed in a case where an alternate molecular basis for disease was identified.
BP6	Met	This variant is classified as Likely benign in ClinVar by GeneDx (VariationID: 386695), a clinical diagnostic laboratory. The classification is supported by in silico evidence indicating a conservative change at a poorly conserved position. While a single submitter, GeneDx is a reputable clinical laboratory whose classification constitutes supporting evidence for a benign interpretation.	clinvar
BP7	Met	NM_001128425.2:c.690+12G>T is an intronic variant at position +12, outside the conserved splice consensus region. SpliceAI predicts no impact on splicing (max delta score = 0.00), with no predicted donor/acceptor gain or loss. This is consistent with a silent intronic change with no predicted functional consequence on splicing.	spliceai

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