NM_006361.6:c.567C>T is a synonymous variant in HOXB13 (p.Asn189=) that does not alter the amino acid sequence.

This variant is extremely rare in population databases, present at an allele frequency of 0.00991% in gnomAD v2.1 (28/282,626 alleles) and 0.00452% in gnomAD v4.1 (73/1,614,196 alleles), with no homozygotes observed, satisfying PM2 at supporting level.

Multiple reputable clinical diagnostic laboratories (8 independent submissions) have classified this variant as Benign or Likely benign in ClinVar (VariationID 483492), with the underlying variant-specific evidence not publicly available for independent evaluation, satisfying BP6 at supporting level.

SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with the synonymous nature of this variant.

No functional studies, cosegregation data, de novo observations, case-control studies, or computational evidence supporting pathogenicity have been identified for this variant.

The variant lies at codon 189, outside the HOXB13 homeodomain (aa 195-254), and does not fall within a known mutational hotspot or functionally critical domain.

Bulk evidence is sparse: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP6) are met, yielding a net indeterminate ACMG/AMP classification by strict criteria counting. However, the unanimous benign/likely benign consensus from 8 independent clinical laboratories strongly supports a benign interpretation.