NM_006361.6:c.567C>T

HOXB13 · NP_006352.2:p.(Asn189=) · NM_006361.6

GRCh37: chr17:46805389 G>A · GRCh38: chr17:48728027 G>A

Gene: HOXB13 Transcript: NM_006361.6

Final call

VUS

PM2 supporting BP6 supporting

Variant details

Gene

HOXB13

Transcript

NM_006361.6

Protein

NP_006352.2:p.(Asn189=)

gnomAD AF

4.522375225809009e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	NM_006361.6:c.567C>T is a synonymous variant (p.Asn189=) that does not introduce a premature termination codon, disrupt an initiator codon, or alter a canonical splice site. Per ClinGen SVI PVS1 recommendations (PMC6185798), this variant does not fall into any null-variant bucket, and the automated PVS1 assessment confirms it is not eligible for generic PVS1 framework application.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies when the same amino acid change has been established as pathogenic via a different nucleotide change. This variant is synonymous (p.Asn189=) and does not alter the amino acid sequence; there is no pathogenic amino acid change at this position to compare against.
PS2	Not met	No de novo occurrences of NM_006361.6:c.567C>T have been reported in ClinVar, the published literature, or public databases. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed in a patient with the disease and no family history.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies have been published demonstrating a damaging effect of c.567C>T on HOXB13 protein function or splicing. SpliceAI predicts no splicing impact (max delta score = 0.00). No VCEP/CSPEC functional dataset exists for HOXB13.	spliceai
PS4	Not met	No case-control studies have been identified comparing the prevalence of c.567C>T in affected individuals versus controls for any HOXB13-associated phenotype (e.g., prostate cancer). The variant is rare in population databases (AF ~0.01% in gnomAD v2.1, ~0.005% in v4.1), which does not provide positive evidence for PS4.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 applies when a novel missense change occurs at an amino acid residue where a different missense change has been established as pathogenic. This variant is synonymous (p.Asn189=) and does not alter the amino acid; it represents a less severe molecular consequence than any potential missense change at this position.
PM1	Not met	The variant is located at codon 189 (Asn189), which lies outside the HOXB13 homeodomain (amino acids 195-254). The region surrounding codon 189 is not an established mutational hotspot, and no evidence supports that this codon resides in a well-characterized functional domain without benign variation.
PM2	Met	This variant is present at extremely low frequency in population databases. In gnomAD v2.1, the allele frequency is 0.00991% (28/282,626 alleles, 0 homozygotes; grpmax FAF=0.0715%). In gnomAD v4.1, the allele frequency is 0.00452% (73/1,614,196 alleles, 0 homozygotes; grpmax FAF=0.0589%). Both global AF and grpmax FAF are well below the 0.1% threshold for PM2. It is absent from gnomAD-Canada v1.0. The highest sub-population frequency is in the African/African American population (v2.1: 0.10%, v4.1: 0.075%).	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a novel missense change at the same amino acid residue as a known pathogenic missense variant. This variant is synonymous (p.Asn189=) and does not alter the amino acid. The automated PM5 candidate harvesting confirmed no eligible same-residue comparators.	pm5_candidates
PM6	Not met	No reported instances of de novo occurrence of c.567C>T (without confirmation of paternity and maternity) have been identified in ClinVar, the published literature, or public databases.	clinvar
PP1	Not met	No published cosegregation data have been identified for c.567C>T with any HOXB13-associated disease phenotype. No family studies or LOVD entries documenting segregation of this variant with disease were found.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. This variant is synonymous (p.Asn189=), not missense.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this variant. The HCI prior is not supported for HOXB13. No computational tool predicts a pathogenic effect.	spliceai
PP4	Not met	No patient-specific phenotype or family history data are available to evaluate whether the clinical presentation is highly specific for a disease with a single genetic etiology. PP4 requires detailed phenotypic information that was not provided for this case.
PP5	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic with evidence not available for independent evaluation. In ClinVar (VariationID 483492), this variant is reported as Likely benign by 4 clinical laboratories, Benign by 3 clinical laboratories, and benign by 1 clinical laboratory. No reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	The maximum allele frequency observed in any population is 0.10% (African/African American, gnomAD v2.1), which is well below the 1% threshold for BA1. The grpmax FAF is 0.0715% (v2.1) and 0.0589% (v4.1), both far below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency observed is 0.10% (African/African American, gnomAD v2.1), which is below the 0.3% threshold for BS1 under non-VCEP generic ACMG rules. The grpmax FAF is 0.0715% (v2.1) and 0.0589% (v4.1), both below 0.3%. While present in population databases, the frequency does not exceed the expected threshold for a disorder-associated variant.	gnomad_v2 gnomad_v4
BS2	Not met	No specific observations of this variant in healthy adult individuals for a disorder with full penetrance expected at an early age have been identified. While the variant is observed in gnomAD (a population database largely composed of individuals not ascertained for severe pediatric disease), the lack of detailed phenotype data for carriers precludes meeting BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies have been published demonstrating that c.567C>T has no damaging effect on HOXB13 protein function or mRNA splicing. While SpliceAI predicts no splicing impact (max delta = 0.00), this is in silico prediction, not experimental functional evidence. The absence of this variant from COSMIC (somatic cancer database) and OncoKB (Unknown Oncogenic Effect) does not constitute functional evidence.	spliceai
BS4	Not met	No published family segregation analyses demonstrating lack of segregation of c.567C>T with an HOXB13-associated phenotype have been identified. BS4 requires specific evidence of non-segregation in affected families.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants are known to cause disease. This variant is synonymous (p.Asn189=), not missense. Additionally, HOXB13-associated disease (prostate cancer risk) involves both missense (e.g., G84E) and other variant types.
BP2	Not met	No reported observations of c.567C>T in trans with a known pathogenic HOXB13 variant (for a dominant disorder) or in cis with a pathogenic variant in any inheritance pattern. No co-occurrence data with established pathogenic HOXB13 variants were identified in ClinVar, literature, or public databases.	clinvar
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. While SpliceAI predicts no splicing impact (max delta = 0.00) for this synonymous variant, this represents only a single line of computational evidence. Conservation data (GERP, phyloP, PhastCons), REVEL, and BayesDel are not available to provide additional computational support. A single line of in silico evidence is insufficient to meet the 'multiple lines' requirement of BP4.	spliceai
BP5	Not assessed	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No case-specific clinical or molecular data were provided for the individual in whom this variant was identified, and no alternate molecular diagnosis has been documented.
BP6	Met	Multiple reputable clinical diagnostic laboratories have independently classified NM_006361.6:c.567C>T as Benign or Likely benign in ClinVar (VariationID 483492). Specifically: 4 clinical laboratories classify as Likely benign (GeneDx, Ambry Genetics, KCCC/NGS Laboratory, Sinai Health System), 3 as Benign (Labcorp/Women's Health and Genetics, Myriad Genetics), and 1 as benign (Quest Diagnostics). These are established clinical testing laboratories with criteria-provided classifications. The underlying variant-specific evidence used by these laboratories is not publicly available for independent evaluation, satisfying the BP6 requirement.	clinvar
BP7	Not met	BP7 requires both (1) splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site, AND (2) the nucleotide is not highly conserved. The first condition is satisfied: SpliceAI predicts no splicing impact (max delta = 0.00). However, the second condition cannot be evaluated because no nucleotide-level conservation data (GERP, phyloP, PhastCons) are available for this genomic position. Without conservation evidence, BP7 cannot be fully met.	spliceai

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