Variant classification summary

NM_003000.3:c.73-29del

SDHB · NP_002991.2:p.? · NM_003000.3

GRCh37: chr1:17371411 GA>G · GRCh38: chr1:17044916 GA>G

Gene: SDHB Transcript: NM_003000.3

Final call

VUS

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.?

gnomAD AF

0.000786436882320673 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

No ACMG/AMP criteria were met; with no pathogenic or benign combination threshold satisfied, the variant is classified as a variant of uncertain significance (VUS).

Final determination: With no applied criteria, the generic ACMG/AMP 2015 fallback rules classify the variant as VUS because no pathogenic, likely pathogenic, benign, or likely benign combination threshold is met.

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	Not met: intronic one-base deletion with no predicted protein change and SpliceAI max delta 0.002, not a null or splice-disrupting variant.	cspec pvs1_generic_framework pvs1_variant_assessment spliceai PMID:25741868
PS1	N/A	Not applicable: intronic variant with no predicted protein change, so no same-residue amino-acid comparison is possible.	cspec
PS2	Not assessed	Not assessed: no parental genotype or pedigree evidence establishes a de novo origin in the proband.	cspec clinvar
PS3	Not assessed	Not assessed: no validated variant-specific functional assay evidence was available.	cspec PMID:25741868
PS4	Not assessed	Not assessed: no case-control or enrichment evidence for this variant was available.	cspec
PM1	N/A	Not applicable: intronic variant with no protein residue to assess against critical domains or hotspots.	cspec
PM2	Not met	Not met: gnomAD v4.1 reports 1253 alternate alleles with two homozygotes, so the variant is not absent from controls.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: SDHB disease is autosomal dominant here, and PM3 requires recessive inheritance.	cspec
PM4	Not met	Not met: intronic deletion with no predicted protein-length change, not an in-frame coding indel.	cspec spliceai PMID:25741868
PM5	N/A	Not applicable: no predicted amino-acid change, so no pathogenic missense at the same residue to compare.	cspec
PM6	Not assessed	Not assessed: no case documentation of presumed de novo occurrence with incomplete parental testing.	cspec clinvar
PP1	Not assessed	Not assessed: no family or segregation data were available for this variant.	cspec
PP2	N/A	Not applicable: not a missense variant, which PP2 requires.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.002 shows no predicted splice effect.	spliceai
PP4	Not assessed	Not assessed: no proband or carrier phenotype was provided to assess specificity.	cspec
PP5	Not met	Not met: ClinVar has no expert-panel pathogenic or likely pathogenic assertion for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum population allele frequency 0.00098 (0.098%) is below the 1% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: highest observed frequency 0.098% (gnomAD v4.1 European non-Finnish) is below the 0.3% BS1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: two gnomAD homozygotes are reported, but their unaffected status could not be confirmed.	gnomad_v4
BS3	Not assessed	Not assessed: no functional study demonstrating preserved SDHB function was available.	cspec PMID:25741868
BS4	Not assessed	Not assessed: no phenotype-confirmed non-segregation analysis was available.	cspec
BP1	N/A	Not applicable: not a missense variant; BP1 applies only to missense changes.	cspec
BP2	Not assessed	Not assessed: no genotype or phase data establish an allelic relationship with a pathogenic variant.	cspec
BP3	Not met	Not met: no in-frame coding repeat-region indel is established for this intronic deletion.	cspec spliceai PMID:25741868
BP4	Not assessed	Not assessed: SpliceAI max delta 0.002 is low, but no verified calibration supports a benign call from this single predictor.	spliceai cspec
BP5	Not assessed	Not assessed: no evidence that another molecular diagnosis explains the phenotype.	cspec
BP6	Not met	Not met: ClinVar has no expert-panel benign or likely benign assertion for this exact variant.	clinvar
BP7	N/A	Not applicable: intronic deletion, not a synonymous coding variant as BP7 requires.

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.