NM_001933.5:c.236C>T

DLST · NP_001924.2:p.(Ala79Val) · NM_001933.5

GRCh37: chr14:75356014 C>T · GRCh38: chr14:74889311 C>T

Gene: DLST Transcript: NM_001933.5

Final call

VUS

PM2 supporting

Variant details

Gene

DLST

Transcript

NM_001933.5

Protein

NP_001924.2:p.(Ala79Val)

gnomAD AF

1.2413817074957111e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: gnomAD v4.1 allele frequency is 1.24e-06 with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet a pathogenic, likely pathogenic, likely benign, or benign combination, so the result is VUS.

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	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001933.5:c.236C>T in DLST is a missense substitution predicted to produce NP_001924.2:p.(Ala79Val). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no documented pathogenic same-amino-acid comparator was available for the DLST Ala79Val substitution.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband phenotype or parental genotype results establish de novo occurrence of NM_001933.5:c.236C>T.
PS3	Not assessed	Not assessed: no variant-specific functional assay, validated control comparison, or biological assay result is available for NM_001933.5:c.236C>T.
PS4	Not assessed	Not assessed: no affected-case series, control comparison, odds ratio, or statistically significant enrichment value is available for this exact variant.
PM1	Not assessed	Not assessed: no governing DLST domain table was available and no statistically significant hotspot was identified at residue 79.
PM2	Met	Met at supporting strength: gnomAD v4.1 allele frequency is 1.24e-06, below the <=0.0001 PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic allele, or informative trans phase is documented for this DLST variant.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001933.5:c.236C>T in DLST is a missense substitution predicted to produce NP_001924.2:p.(Ala79Val). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: zero same-residue comparator variants were available, so no pathogenic alternate change at DLST residue 79 could be evaluated.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no affected individual or parental testing documents a presumed de novo occurrence for this DLST variant.
PP1	Not assessed	Not assessed: no pedigree, informative meioses, or affected-relative genotypes are available to demonstrate cosegregation.
PP2	Not assessed	Not assessed: no validated DLST-specific evidence establishes a predominant missense disease mechanism or low benign missense rate.
PP3	Not met	Not met: REVEL 0.519 is below the 0.644 supporting PP3 threshold for missense variants.	revel
PP4	Not assessed	Not assessed: no individual phenotype or clinical diagnosis is provided to evaluate specificity for a DLST-related disorder.
PP5	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel Pathogenic or Likely pathogenic assertion exists to support PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 1.24e-06, far below the >=0.05 BA1 threshold.	gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 allele frequency is 1.24e-06, below the >=0.01 generic BS1 threshold.	gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes, which is absence of positive BS2 evidence rather than benign homozygote observation.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific functional assay, validated control comparison, or preserved-function result is available for NM_001933.5:c.236C>T.
BS4	Not assessed	Not assessed: no affected-family genotypes or phenotype data demonstrate non-segregation of the DLST variant.
BP1	Not assessed	Not assessed: no validated DLST framework establishes that disease is restricted to truncating variants and excludes a missense mechanism.
BP2	Not assessed	Not assessed: no documented cis or trans relationship with a pathogenic variant, or affected individual with an alternate pathogenic explanation, is available.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001933.5:c.236C>T in DLST is a missense substitution predicted to produce NP_001924.2:p.(Ala79Val). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.519 exceeds the 0.29 supporting BP4 threshold for missense variants.	revel
BP5	Not assessed	Not assessed: no individual phenotype or documented alternate molecular basis is available to evaluate whether another cause explains the disorder.
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel Benign or Likely benign assertion exists to support BP6.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001933.5:c.236C>T in DLST is a missense substitution predicted to produce NP_001924.2:p.(Ala79Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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