NM_003000.3:c.158G>A

SDHB · NP_002991.2:p.(Gly53Glu) · NM_003000.3

GRCh37: chr1:17371298 C>T · GRCh38: chr1:17044803 C>T

Gene: SDHB Transcript: NM_003000.3

Final call

Benign

BA1 stand-alone benign

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.(Gly53Glu)

gnomAD AF

0.0002837610607954975 (v4.1)

ClinVar

Benign

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

BA1 (Stand-alone benign): Ashkenazi Jewish allele frequency ~1.1% in gnomAD v4.1 (325/29,608 alleles) and v2.1 (112/10,370) exceeds the 1.0% threshold; far too common for a pathogenic autosomal-dominant SDHB allele.

Overall classification: Benign, from BA1 stand-alone under generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules classify a variant as Benign when BA1 (stand-alone benign) 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	N/A	Not applicable: c.158G>A is a missense substitution, not a null variant class (nonsense, frameshift, or splice-consensus) to which PVS1 applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: ClinVar has no pathogenic submissions for this amino acid change; 13 labs call it Benign or Likely benign, none P/LP.	clinvar PMID:41252211
PS2	Not assessed	Not assessed: no proband phenotype or de novo testing data were available.	cspec
PS3	Not assessed	Not assessed: no functional assay data for this variant were available; the reviewed SDHB functional study did not test p.Gly53Glu.
PS4	Not assessed	Not assessed: no exact-variant affected-case count with appropriate controls was available to calculate enrichment.	PMID:19802898 PMID:23072324
PM1	Not met	Not met: cancerhotspots.org reports no significant hotspot at SDHB codon 53, and Gly53 is not among the Fe-S cluster-binding cysteines.	PMID:41252211 cspec
PM2	Not met	Not met: allele frequency ~1.1% (Ashkenazi Jewish, gnomAD v4.1 and v2.1) far exceeds the <0.1% PM2 rarity threshold.	gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: SDHB-related disease is autosomal dominant, but PM3 requires observations in a recessive disorder.	cspec
PM4	N/A	Not applicable: this missense substitution does not change protein length, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate substitution at codon 53 with established pathogenicity was found; flagged for human review.	pm5_candidates
PM6	Not assessed	Not assessed: no reported de novo occurrence or parental testing result was available.	cspec
PP1	Not assessed	Not assessed: no informative relatives, genotypes, or segregation data were reported.	cspec
PP2	Not assessed	Not assessed: no gene-level missense-constraint metric or VCEP position on PP2 was available; flagged for human review.	cspec
PP3	Not met	Not met: REVEL 0.608 is below the PP3 supporting threshold (>=0.644) and above the BP4 threshold, an indeterminate zone.	revel spliceai cspec
PP4	Not assessed	Not assessed: no case-level phenotype was supplied to evaluate phenotype specificity.	cspec
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists for this variant.	clinvar
BA1	Met	Met (stand-alone benign): Ashkenazi Jewish allele frequency 1.10% in gnomAD v4.1 (325/29,608 alleles) exceeds the 1.0% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	N/A	Not applicable: BA1 already provides stand-alone benign evidence from the same population-frequency data.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: homozygotes are documented in gnomAD, but no phenotyped unaffected adult observations were available.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal activity for this variant were available.
BS4	Not assessed	Not assessed: no informative non-segregation observations were reported.	cspec
BP1	Not met	Not met: missense is an established disease mechanism in SDHB; 27 pathogenic missense variants were functionally validated, so BP1's premise does not apply.	PMID:41252211
BP2	Not assessed	Not assessed: no variant co-occurrence or phase data were available.
BP3	N/A	Not applicable: c.158G>A is a missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.608 is above the BP4 supporting threshold (<=0.29-0.30), so it provides no benign in-silico support.	revel spliceai cspec
BP5	Not assessed	Not assessed: no alternative molecular diagnosis was documented for the affected individual.
BP6	Not met	Not met: no ClinVar expert-panel Benign or Likely benign assertion exists for this variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, but c.158G>A is a missense substitution.	generic_acmg_combination_rules

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.