Variant classification summary

NM_000518.5:c.79G>A

HBB · NP_000509.1:p.(Glu27Lys) · NM_000518.5

GRCh37: chr11:5248173 C>T · GRCh38: chr11:5226943 C>T

Gene: HBB Transcript: NM_000518.5

Final call

VUS

PS4 strong PP3 supporting

Variant details

Gene

HBB

Transcript

NM_000518.5

Protein

NP_000509.1:p.(Glu27Lys)

gnomAD AF

0.00022370616040909101 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PS4 strong is supported by an affected-versus-matched-ancestry OR of 188.51 with a 95% CI excluding 1.

2

VUS: PP3 supporting is supported by REVEL 0.721, above the calibrated threshold of 0.644.

Final determination: Under generic ACMG/AMP 2015 rules, one strong pathogenic criterion plus one supporting criterion satisfies no pathogenic or likely pathogenic combination, while no benign rule is satisfied, resulting in 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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no distinct pathogenic nucleotide change producing the same Glu27Lys substitution was documented beyond the observed c.79G>A allele.	PMID:27828729 pm5_candidates
PS2	Not assessed	Not assessed: no documented maternity and paternity confirmation for an affected proband with this variant.
PS3	Not assessed	Not assessed: the review reports aberrant splicing and reduced betaE-mRNA but provides no controlled, reproducible variant-specific assay data meeting the PS3 definition.	PMID:17278112
PS4	Met	Met: affected-versus-matched-ancestry control counts yield OR 188.51 (95% CI 139.95-253.93), and 188.51 > 5.0 with the interval excluding 1.0.	PMID:27828729 gnomad_v4
PM1	Not assessed	Not assessed: residue 27 lacks documented hotspot evidence and no qualifying critical domain without benign variation was established under the generic rule.	cspec hotspots
PM2	Not met	Not met: gnomAD v4.1 overall AF is 0.000223706, exceeding the PM2 supporting threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: 60 compound-heterozygous patients were reported, but parental or offspring testing confirming trans phase was not documented.	PMID:27828729
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: zero same-residue comparator candidates were found, and the documented Glu>Ala alternative was not established as pathogenic.	PMID:15481887 pm5_candidates
PM6	Not assessed	Not assessed: no case-level evidence shows this variant was assumed de novo without parental genotype confirmation.
PP1	Not assessed	Not assessed: no affected relatives with documented co-segregation or informative meioses are reported.
PP2	Not assessed	Not assessed: HBB missense disease variation is documented, but a low gene-level benign missense rate was not established.	PMID:25052315 PMID:27828729 gnomad_v4
PP3	Met	Met at supporting strength: REVEL 0.721 meets the missense PP3 threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history needed to judge high specificity for a single-gene disease are not provided.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification, only laboratory submissions and an aggregate Pathogenic label.	clinvar PMID:25052315
BA1	Not met	Not met: the highest observed gnomAD population frequency is 0.002580149, far below the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 overall AF is 0.000223706 and the South Asian maximum is 0.002580149, both below the 0.01 default BS1 threshold.	gnomad_v2 gnomad_v4 PMID:27828729
BS2	Not assessed	Not assessed: gnomAD reports five homozygotes, but it does not establish that they were healthy adults without HBB-related disease.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no controlled functional study demonstrates absence of damage to protein function or splicing, while the reviewed source describes abnormal splicing and reduced betaE-mRNA.	PMID:17278112
BS4	Not assessed	Not assessed: no affected relatives with documented absence of this variant are reported.
BP1	Not met	Not met: HBB disease evidence includes established point/missense variants such as Glu27Lys, not primarily truncating variants alone.	PMID:25052315 PMID:27828729
BP2	Not assessed	Not assessed: compound-heterozygous recessive cases were reported, but no cis observation or fully penetrant dominant trans context was established.	PMID:27828729
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.721 exceeds the missense BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no documented case links this variant with a confirmed alternate molecular basis for the patient's disease.
BP6	Not met	Not met: no exact-variant expert-panel benign or likely-benign report is present; the audited laboratory submissions are Pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	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.