Variant classification summary

NM_000545.8:c.872dup

HNF1A · NP_000536.6:p.(Gly292ArgfsTer25) · NM_000545.8

GRCh37: chr12:121432117 G>GC · GRCh38: chr12:120994314 G>GC

Gene: HNF1A Transcript: NM_000545.8

Final call

Benign

BA1 stand-alone benign BS1 strong

Variant details

Gene

HNF1A

Transcript

NM_000545.8

Protein

NP_000536.6:p.(Gly292ArgfsTer25)

gnomAD AF

5.23566083389118e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 (stand-alone benign) exceeds the HNF1A VCEP population-frequency threshold using the adjudicated gnomAD v2.1 value.

2

Benign: BS1 (strong) exceeds the HNF1A VCEP population-frequency threshold using the adjudicated gnomAD v2.1 value.

3

PVS1 (very strong) is met for the exon 4 frameshift but does not independently satisfy a pathogenic combination rule.

4

PP5 is adjudicated supporting but is not an eligible HNF1A VCEP pathogenic combination criterion.

Final determination: Under the HNF1A VCEP Version 3.1 framework, one stand-alone benign criterion satisfies Rule 17 for Benign, and no pathogenic rule is satisfied by the adjudicated criteria.

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	Met	Met, very strong: exon 4 frameshift c.872dup lies 5' of c.1714, and the exact P291fsinsC transcript was reduced to 6% of normal by NMD.	cspec vcep_hnf1a_pvs1_decision_tree_20230625 pvs1_variant_assessment PMID:14747304
PS1	N/A	Not applicable: c.872dup causes p.(Gly292ArgfsTer25), a frameshift rather than the same amino-acid change required for PS1.	cspec
PS2	Not assessed	Not assessed: no documented de novo proband, parental testing, or phenotype-consistency point assignment is available for calculating PS2 strength.	cspec vcep_ps2_denovo_points_table
PS3	Not assessed	Not assessed: P291fsinsC RNA fell to 6% of normal, but this patient-cell-line NMD assay is not among the VCEP's approved PS3 assay types.	cspec PMID:14747304
PS4	Not met	Not met: nine unrelated occurrences satisfy PS4 Strong, but gnomAD grpmax FAF 0.00002301 <= 0.000003 PM2_Supporting threshold? no.	cspec PMID:12574234 gnomad_v4
PM1	Not met	Not met: codon 292 lies outside the VCEP PM1 regions, which end at codon 280, and no VCEP hotspot route is specified.	cspec PMID:12574234 PMID:12355088
PM2	Not met	Not met: gnomAD v4.1 grpmax FAF 0.00002301 exceeds the VCEP PM2 threshold of 0.000003, as does v2.1 value 0.00038181.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the HNF1A VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: PM4 covers in-frame amino-acid deletions or insertions, whereas c.872dup is a one-nucleotide frameshift producing a premature termination codon.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: c.872dup is a frameshift, not an amino-acid change eligible for same-residue PM5 comparison.	cspec
PM6	N/A	Not applicable: the HNF1A VCEP explicitly designates PM6 as Not Applicable, regardless of the absence of a variant-specific table entry.	cspec vcep_ps2_denovo_points_table
PP1	Not assessed	Not assessed: nine families and 31 affected individuals were reported, but informative meioses and a cosegregation probability were not provided for comparison with VCEP thresholds.	cspec PMID:12574234
PP2	N/A	Not applicable: the HNF1A VCEP does not support PP2 because its gene-level constraint score is not significant.	cspec
PP3	N/A	Not applicable: c.872dup is a coding frameshift, outside the VCEP PP3 SpliceAI scope for non-canonical splicing or synonymous variants.	cspec
PP4	Not assessed	Not assessed: the required MPC >=50% result and negative HNF4A testing are not available for this patient.	cspec
PP5	Met	Not applicable: the HNF1A VCEP explicitly prohibits use of PP5 for this VCEP.	cspec clinvar
BA1	Met	Met: gnomAD v2.1 grpmax FAF 0.00038181 exceeds the VCEP BA1 threshold of 0.0001, although gnomAD v4.1 reports 0.00002301.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met: gnomAD v2.1 grpmax FAF 0.00038181 exceeds the VCEP BS1 threshold of 0.000033, while gnomAD v4.1 reports 0.00002301.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no normoglycemic genotype-positive individual aged 70 or older is documented, which is required by the VCEP rule.	cspec
BS3	Not assessed	Not assessed: P291fsinsC RNA was 6% of normal, with no VCEP-approved benign assay reaching the BS3 threshold of at least 75% wild-type activity.	cspec PMID:14747304
BS4	Not assessed	Not assessed: no genotype-negative, phenotype-positive family member with an MPC score >50% is documented.	cspec
BP1	N/A	Not applicable: the HNF1A VCEP explicitly marks BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: no documented likely pathogenic second variant or cis/trans phase is available for NM_000545.8:c.872dup.	cspec
BP3	N/A	Not applicable: the HNF1A VCEP explicitly designates BP3 as Not Applicable for this framework.	cspec
BP4	N/A	Not applicable: c.872dup is a coding frameshift, so a low SpliceAI max delta of 0.014 cannot support no impact on the gene product.	cspec
BP5	Not assessed	Not assessed: no pathogenic or likely pathogenic variant in another monogenic diabetes gene is documented.	cspec
BP6	N/A	Not applicable: the HNF1A VCEP explicitly prohibits use of BP6 for this VCEP.	cspec
BP7	N/A	Not applicable: c.872dup is a coding frameshift, not a non-protein-altering variant for which the VCEP BP7 SpliceAI and phyloP100 rule applies.	cspec

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.