NM_000546.6:c.370C>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

Variant normalization failed: Mutalyzer returned HTTP 422, and VariantValidator reported a ReferenceMismatchError (reference base at NM_000546.6:c.370 is T, not C). The gene, protein consequence, and genomic coordinates could not be resolved.

PVS1 is not applicable — NM_000546.6:c.370C>T is a substitution variant, not a null variant eligible for PVS1 consideration.

All other criteria could not be assessed. Population databases (gnomAD v2.1, v4.1), ClinVar, in silico predictors (REVEL, BayesDel, SpliceAI), functional databases (COSMIC, OncoKB, Hotspots), and the published literature returned no usable evidence for this variant because gene/coordinate lookup prerequisites were not met.

No classification can be assigned. The variant cannot be evaluated under ACMG/AMP 2015 criteria without successful normalization. Manual review is required: confirm the correct HGVS expression (NM_000546.6:c.370C>T may have an incorrect reference base), re-run normalization, and re-attempt all evidence gathering.

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	N/A	PVS1 applies only to null variants (nonsense, frameshift, canonical splice site, initiation codon, single/multi-exon deletion). NM_000546.6:c.370C>T is a substitution; without evidence of a stop-gain or splice-disrupting consequence, PVS1 is not applicable.
PS1	Not assessed	Cannot assess. Variant normalization failed (Mutalyzer HTTP 422; VariantValidator reports reference base at NM_000546.6:c.370 is T, not C, causing a ReferenceMismatchError). No protein consequence could be determined, and no alternate pathogenic variants at the same residue are available for comparison.
PS2	Not assessed	Cannot assess. No de novo observations for this variant were found in the literature or clinical databases. No publications were identified for this variant.
PS3	Not assessed	Cannot assess. No functional assay data (well-established in vitro or in vivo studies) were identified for this variant. No publications were retrieved.
PS4	Not assessed	Cannot assess. No case-control or cohort prevalence data were available. gnomAD v2.1 and v4.1 lookups did not complete, and no publications with affected-individual counts were identified.
PS5	Not assessed	Cannot assess. No ClinVar entry or reputable source classification was found for this variant. ClinVar lookup was skipped due to normalization failure.
PM1	Not assessed	Cannot assess. The protein domain and residue position could not be determined due to normalization failure, so location within a mutational hot spot or critical functional domain cannot be confirmed.
PM2	Not assessed	Cannot assess. gnomAD v2.1 and v4.1 allele frequency data are unavailable (queries did not complete). gnomAD-Canada v1.0 reports the variant as absent (AC=0, AN=0), but this is a small reference set and cannot substitute for the full gnomAD databases. A definitive PM2 determination cannot be made.
PM5	Not assessed	Cannot assess. Protein residue context could not be resolved due to normalization failure. The automated PM5 candidate harvesting was unsuccessful — no same-residue comparator variants were identified.
PM6	Not assessed	Cannot assess. No de novo observations (with confirmed maternity and paternity) were identified for this variant in any available source.
PP1	Not assessed	Cannot assess. No cosegregation data (family studies showing the variant tracks with disease) were available.
PP2	Not assessed	Cannot assess. The gene and its missense constraint metrics (z-score, benign missense rate) could not be determined due to normalization failure. PP2 requires a low rate of benign missense variation in the gene.
PP3	Not assessed	Cannot assess. In silico predictors (REVEL, BayesDel, SpliceAI) could not be queried because genomic coordinates were not available due to normalization failure. No computational evidence of deleterious effect can be generated.
PP4	Not assessed	Cannot assess. No phenotypic data (patient presentation, family history, disease specificity) were provided or identified for this variant.
PP5	Not assessed	Cannot assess. No reputable source (ClinVar expert panel, clinical laboratory, or published study) has classified this variant as pathogenic. ClinVar lookup was skipped due to normalization failure.
BA1	Not assessed	Cannot assess. gnomAD v2.1 and v4.1 allele frequency data are unavailable. BA1 requires an allele frequency >1% in population databases, but the necessary data could not be retrieved.
BS1	Not assessed	Cannot assess. gnomAD v2.1 and v4.1 allele frequency data are unavailable. BS1 requires an allele frequency >0.3% in population databases, but the necessary data could not be retrieved.
BS2	Not assessed	Cannot assess. No observations of this variant in healthy adults (in trans with a pathogenic variant for a fully penetrant dominant disorder, or in a homozygous state) were identified.
BS3	Not assessed	Cannot assess. No well-established functional studies demonstrating no damaging effect were identified for this variant.
BS4	Not assessed	Cannot assess. No segregation data demonstrating lack of cosegregation with disease were available.
BP1	Not assessed	Cannot assess. The gene and its disease mechanism (truncating vs missense) could not be determined due to normalization failure. BP1 requires a gene where primarily truncating variants cause disease.
BP2	Not assessed	Cannot assess. No observations of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder were identified.
BP4	Not assessed	Cannot assess. In silico predictors (REVEL, BayesDel, SpliceAI) could not be queried because genomic coordinates were unavailable due to normalization failure. No computational evidence suggesting a benign effect can be generated.
BP5	Not assessed	Cannot assess. No cases were identified in which this variant was found in an individual with an alternate molecular basis for disease.
BP6	Not assessed	Cannot assess. No reputable source (ClinVar, clinical laboratory, or published study) has classified this variant as benign. ClinVar lookup was skipped due to normalization failure.
BP7	Not assessed	Cannot assess. BP7 applies to synonymous (silent) variants with no predicted splice impact. The protein consequence of NM_000546.6:c.370C>T could not be determined due to normalization failure, so it is unknown whether this substitution is synonymous or missense.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.