NM_000077.5:c.290A>T

· ·

GRCh37: None · GRCh38: None

Gene: Transcript:

Final call

VUS

Variant details

Gene

Transcript

Protein

gnomAD AF

ClinVar

None

OncoKB

None

Classification rationale

Interpretation summary

Generated evidence synthesis

No ACMG/AMP criteria could be met or ruled out for NM_000077.5:c.290A>T due to a critical normalization failure during case preparation: VariantValidator was unavailable and the gene, genomic coordinates, protein consequence, and all downstream evidence sources (gnomAD v2.1/v4.1, ClinVar, REVEL, BayesDel, SpliceAI, COSMIC, OncoKB, Hotspots, literature) could not be resolved. The variant cannot be classified and requires complete re-analysis when normalization services are available.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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
PVS1	Not assessed	Gene could not be resolved during normalization (VariantValidator unavailable); loss-of-function mechanism eligibility and variant class (nonsense/frameshift/canonical splice) could not be determined. PVS1 gene gate is manual_review_required.
PS1	Not assessed	No ClinVar data available to identify a known pathogenic variant with the same amino acid change; protein consequence could not be resolved during normalization.
PS2	Not assessed	No literature or database evidence of de novo occurrence for this variant was identified; no publications were retrieved for review.
PS3	Not assessed	No functional studies were identified for this variant; no publications, OncoKB, or ClinVar functional evidence available.
PS4	Not assessed	No prevalence or case-control data available; no ClinVar submissions, no publications, and no cohort data retrieved.
PS5	Not assessed	Requires a reported pathogenic variant at the same nucleotide position from a reputable source; no ClinVar or literature data available.
PM1	Not assessed	Gene and protein domain architecture could not be resolved; the variant's location relative to known mutational hotspots or critical functional domains is unknown.
PM2	Not assessed	gnomAD v2.1 and v4.1 queries failed because normalization did not resolve genomic coordinates. gnomAD-Canada returned AC=0/AN=0 (no coverage), not a true absence call. Population frequency cannot be determined.
PM5	Not assessed	Protein residue context could not be determined; automatic PM5 candidate harvesting was skipped because classic same-residue missense semantics could not be confirmed.
PM6	Not assessed	No de novo reports (with or without paternity confirmation) were identified for this variant in any database or publication source.
PP1	Not assessed	No cosegregation data available; no family studies or pedigrees identified for this variant.
PP2	Not assessed	Cannot assess whether this is a missense variant in a gene with a low rate of benign missense variation — gene not identified and HCI prior score unavailable.
PP3	Not assessed	No in silico scores available: REVEL, BayesDel, SpliceAI, and HCI prior all failed or were skipped because genomic coordinates could not be resolved.
PP4	Not assessed	No phenotype data available; no patient descriptions, clinical presentations, or disease associations could be evaluated.
PP5	Not assessed	No ClinVar submissions and no publications reporting this variant as pathogenic from a reputable source.
BA1	Not assessed	Population allele frequency cannot be determined; gnomAD v2.1 and v4.1 queries failed due to normalization failure.
BS1	Not assessed	Population allele frequency cannot be determined; gnomAD v2.1 and v4.1 queries failed due to normalization failure.
BS2	Not assessed	No data on observation in healthy adult individuals; no cohort or control data available.
BS3	Not assessed	No functional studies identified showing no deleterious effect; no publications, OncoKB, or functional assay data available.
BS4	Not assessed	No segregation data available to evaluate lack of cosegregation with disease.
BP1	Not assessed	Cannot determine if this is a missense variant in a gene where primarily truncating variants cause disease; gene identity and disease mechanism unknown.
BP2	Not assessed	No data on observation in trans with a known pathogenic variant; no phase or genotype data available.
BP3	N/A	This variant is a substitution, not an in-frame indel; BP3 applies only to in-frame deletions/insertions in repetitive regions without a known function.
BP4	Not assessed	No in silico scores available: REVEL, BayesDel, and SpliceAI all failed or were skipped because genomic coordinates and gene could not be resolved.
BP5	Not assessed	No data available on cases where this variant is found with an alternate molecular cause for the phenotype.
BP6	Not assessed	No ClinVar submissions or publications reporting this variant as benign from a reputable source.
BP7	N/A	This is a substitution variant that is highly unlikely to be synonymous and lacks splice prediction data; BP7 is reserved for synonymous (silent) variants with no predicted splice impact.
PM3	N/A	No trans/cis phase data available and no evidence of recessive disorder context; PM3 requires observation in trans with a pathogenic variant.
PM4	N/A	This variant is a substitution, not an in-frame indel or stop-loss variant; PM4 applies only to protein-length-altering non-null variants.

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