Variant classification summary

NM_005247.2:c.310C>T

FGF3 · NP_005238.1:p.(Arg104Ter) · NM_005247.2

GRCh37: chr11:69631102 G>A · GRCh38: chr11:69816334 G>A

Gene: FGF3 Transcript: NM_005247.2

Final call

Likely Pathogenic

PM2 moderate PM3 moderate PP1 supporting PP4 supporting

Variant details

Gene

FGF3

Transcript

NM_005247.2

Protein

NP_005238.1:p.(Arg104Ter)

gnomAD AF

1.4874109257769553e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Moderate): ultra-rare population frequency (0.0015% in gnomAD v4.1, zero homozygotes), far below the 0.1% cutoff.

2

PM3 (Moderate): in trans with p.Y49C in an affected compound-heterozygous proband and homozygous in additional affected individuals across two families.

3

PP1 (Supporting): cosegregation with LAMM syndrome in 7 or more affected individuals across 3 unrelated families.

4

PP4 (Supporting): highly specific single-etiology LAMM phenotype (labyrinthine aplasia, microtia, microdontia) in carriers of this exact variant.

5

Combination of 2 moderate + 2 supporting criteria yields Likely Pathogenic under the generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 (PMID:25741868) combination rule applied as fallback: 2 moderate (PM2 + PM3) + 2 supporting (PP1 + PP4) pathogenic criteria, with no met benign criteria, satisfies the '2 Moderate and 2 Supporting' Likely Pathogenic combination.

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	Not assessed	Not assessed: insufficient evidence was available to score the predicted protein-truncating effect; flagged for human review.
PS1	N/A	Not applicable: the nonsense change p.(Arg104Ter) produces no altered amino acid to compare against previously established pathogenic missense variants.	generic_acmg_combination_rules
PS2	N/A	Not applicable: LAMM syndrome is autosomal recessive, so a single de novo heterozygous allele cannot fulfill the disease model, and none is documented.	PMID:17236138 PMID:21306635 PMID:21480479
PS3	Not assessed	Not assessed: no well-established functional study of this variant was found in the reviewed literature.	PMID:25741868 PMID:17236138 PMID:21306635 PMID:21480479 spliceai
PS4	Not met	Not met: affected families and absence from 162 matched controls are qualitative enrichment, not a case-control study with statistical testing.	PMID:17236138 PMID:21306635 PMID:21480479 clinvar
PM1	N/A	Not applicable: as a nonsense variant, no altered residue exists to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (moderate): gnomAD v4.1 allele frequency 0.0015% (zero homozygotes) is far below the 0.1% recessive-disorder cutoff.	gnomad_v2 gnomad_v4 gnomad_canada PMID:21306635 generic_acmg_combination_rules PMID:25741868
PM3	Met	Met (moderate): the variant is in trans with p.Y49C in an affected compound-heterozygous proband and homozygous in additional affected individuals.	PMID:21480479 PMID:17236138 PMID:25741868
PM4	N/A	Not applicable: p.Arg104Ter truncates the protein rather than altering its length, so the protein-length-change criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at Arg104 to compare against a different pathogenic missense change at the same residue.	generic_acmg_combination_rules
PM6	N/A	Not applicable: LAMM syndrome is autosomal recessive and no de novo occurrence of this variant is documented.	PMID:17236138 PMID:21306635 PMID:21480479
PP1	Met	Met (supporting): cosegregates with LAMM syndrome, homozygous or compound heterozygous in 7 or more affected individuals across 3 families.	PMID:17236138 PMID:21306635 PMID:21480479
PP2	N/A	Not applicable: the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.04 is far below the 0.20 splice-altering threshold, and missense predictors do not apply to a stop-gained variant.	spliceai bayesdel PMID:25741868
PP4	Met	Met (supporting): the LAMM phenotype (labyrinthine aplasia, microtia, microdontia) is highly specific to biallelic FGF3 mutations and is seen with this exact variant.	PMID:17236138 PMID:21306635 PMID:21480479 clinvar
PP5	N/A	Not applicable: ClinVar has no expert-panel submissions for this variant, and laboratory classifications alone cannot trigger PP5.	clinvar
BA1	Not met	Not met: the highest population frequency is 0.033% (gnomAD v4.1 Middle Eastern), roughly 30-fold below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS1	Not met	Not met: the highest observed allele frequency (0.033%) is about 9-fold below the >0.3% BS1 cutoff.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1, v4.1, and gnomAD-Canada, and documented homozygotes are all affected with LAMM syndrome.	gnomad_v2 gnomad_v4 gnomad_canada PMID:17236138 PMID:21306635 PMID:21480479 generic_acmg_combination_rules PMID:25741868
BS3	Not assessed	Not assessed: no functional study demonstrating retained or normal activity of the truncated protein was available.	PMID:25741868 spliceai
BS4	Not met	Not met: no affected individual lacks the variant; unaffected relatives are heterozygous carriers or wild-type, as expected for recessive inheritance.	PMID:17236138 PMID:21306635 PMID:21480479
BP1	N/A	Not applicable: the criterion concerns missense variants, and this is a nonsense change (p.Arg104Ter).	generic_acmg_combination_rules
BP2	Not met	Not met: the documented in-trans configurations (compound heterozygosity, homozygosity) are evidence of pathogenicity, the opposite of this criterion.	PMID:25741868 PMID:21480479 PMID:17236138
BP3	N/A	Not applicable: the criterion concerns in-frame indels in repetitive regions; this is a nonsense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: a single negative SpliceAI prediction (max delta 0.04) cannot offset the unambiguous protein-truncating consequence of a stop-gained variant.	spliceai PMID:25741868
BP5	Not assessed	Not assessed: insufficient data were available to determine whether an alternate molecular basis of disease existed in affected cases.
BP6	N/A	Not applicable: no expert-panel benign classification exists for this variant; the ClinVar record is Pathogenic or Likely Pathogenic.	clinvar
BP7	N/A	Not applicable: the criterion applies only to synonymous variants; this nonsense change alters the protein sequence.	generic_acmg_combination_rules

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