NM_005235.2:c.2371A>G

ERBB4 · NP_005226.1:p.(Thr791Ala) · NM_005235.2

GRCh37: chr2:212426744 T>C · GRCh38: chr2:211562019 T>C

Gene: ERBB4 Transcript: NM_005235.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

ERBB4

Transcript

NM_005235.2

Protein

NP_005226.1:p.(Thr791Ala)

gnomAD AF

1.4869575238192008e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005235.2:c.2371A>G (p.Thr791Ala) is a missense variant in exon 20 of ERBB4. It is present at extremely low frequency in population databases (gnomAD v2.1: 3/251,416 alleles, AF=0.00119%; gnomAD v4.1: 24/1,614,034 alleles, AF=0.00149%) with no homozygotes observed, meeting PM2 at supporting strength.

Multiple computational predictors support a benign interpretation: REVEL score of 0.321 is below the pathogenic threshold, BayesDel score of -0.090 is in the benign range, and SpliceAI predicts no splice impact (max delta = 0.00). BP4 is met at supporting strength.

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (LabCorp, Ambry Genetics), each with criteria provided as a single submitter. No expert panel review has been performed.

No functional studies, segregation data, de novo observations, case-control studies, or family co-segregation data are available for this variant. The variant lies within the ERBB4 kinase domain but is not located in a recognized mutational hotspot.

Applying the generic ACMG/AMP 2015 final classification rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in an overall classification of Uncertain Significance. The evidence is balanced and insufficient to classify this variant as either likely pathogenic or likely benign.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	PVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, exon deletion). NM_005235.2:c.2371A>G is a missense variant (p.Thr791Ala) and does not meet the allele-type requirement for PVS1 application.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternate nucleotide change resulting in the same amino acid substitution (p.Thr791Ala) has been reported as pathogenic. No ClinVar entry or publication identifies a different nucleotide change at codon 791 producing Thr791Ala.	clinvar
PS2	Not met	No de novo occurrence of NM_005235.2:c.2371A>G with confirmed paternity and maternity has been reported in the literature or variant databases.
PS3	Not met	No well-established functional studies have been performed to assess the damaging effect of p.Thr791Ala. OncoKB reports no variant-specific reviewed functional evidence, and COSMIC contains no entry for this variant.	oncokb
PS4	Not met	No case-control studies have compared the prevalence of NM_005235.2:c.2371A>G in affected individuals versus general population controls. The variant is present at very low frequency in gnomAD (AF ~0.001%) and has not been enriched in any disease cohort.	gnomad_v2 gnomad_v4
PS5	Not met	No established pathogenic variant at codon 791 with a different amino acid substitution has been identified. No ClinVar entries or publications describe a pathogenic missense change at this residue.	clinvar
PM1	Not met	Although p.Thr791 resides within the ERBB4 protein kinase domain (residues 712–989), the variant is not located in a statistically significant mutational hotspot. Cancer Hotspots database confirms the residue is not significant and the exact variant is not listed. No domain-level constraint metrics (missense Z-score, regional constraint) have been evaluated to demonstrate intolerance of benign missense variation at this position.	oncokb
PM2	Met	This variant is present at extremely low frequency in population databases. gnomAD v2.1 reports 3/251,416 alleles (AF=0.00119%) and gnomAD v4.1 reports 24/1,614,034 alleles (AF=0.00149%), both well below the 0.1% threshold. No homozygotes are observed. gnomAD-Canada v1.0 reports the variant as absent.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic missense variant at codon 791 with a different amino acid change has been identified. PM5 candidate harvesting returned no comparators, and the criterion cannot be applied.	pm5_candidates
PM6	Not met	No presumed de novo occurrence (without confirmation of paternity and maternity) has been reported for NM_005235.2:c.2371A>G in the literature or variant databases.
PP1	Not met	No co-segregation data are available. No multiplex pedigrees demonstrating co-segregation of NM_005235.2:c.2371A>G with a consistent phenotype have been reported.
PP2	Not met	There is insufficient evidence that ERBB4 meets the PP2 criteria: a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. No gene-level missense constraint data (e.g., missense Z-score) have been evaluated to support this criterion.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel score is -0.090 (negative, supporting a benign interpretation), and SpliceAI predicts no splice impact (max delta score = 0.00).	revel bayesdel spliceai
PP4	Not met	No phenotypic data are available for the individual(s) carrying this variant. Without patient phenotype or family history information, specificity for an ERBB4-associated disorder cannot be assessed.
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports this variant as Uncertain significance based on submissions from two clinical laboratories (LabCorp, Ambry Genetics), each with criteria provided, single submitter. No expert panel review has been performed.	clinvar
BA1	Not met	The maximum population allele frequency for NM_005235.2:c.2371A>G is 0.00801% in the African/African American subpopulation (gnomAD v4.1), far below the BA1 threshold of 1%.	gnomad_v4
BS1	Not met	The maximum population allele frequency for NM_005235.2:c.2371A>G is 0.00801% (gnomAD v4.1 African/African American), well below the BS1 threshold of 0.3%.	gnomad_v4
BS2	Not met	No homozygous individuals have been observed in gnomAD (v2.1 or v4.1). No observation of this variant in trans with a known pathogenic variant in a dominant disorder has been documented.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a neutral or benign effect of p.Thr791Ala on protein function have been identified.
BS4	Not met	No segregation data are available to evaluate lack of segregation in affected family members. No family studies have been reported for this variant.
BP1	Not met	ERBB4 is not established as a gene where only truncating variants cause disease. Missense variants in ERBB4 have been implicated in amyotrophic lateral sclerosis (PMID:40469844), and the gene's disease mechanism is not restricted to loss-of-function truncations alone.	pvs1_gene_context
BP2	Not met	No observation of NM_005235.2:c.2371A>G in trans with a pathogenic variant in a gene for a fully penetrant dominant disorder, nor in cis with a pathogenic variant in any inheritance pattern, has been reported.
BP4	Met	Multiple lines of computational evidence support a benign effect. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel score is -0.090 (negative, consistent with a benign interpretation), and SpliceAI predicts no splice impact (max delta score = 0.00).	revel bayesdel spliceai
BP5	Not met	No case has been reported in which NM_005235.2:c.2371A>G is found in an individual with an alternate molecular basis for disease.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar reports this variant as Uncertain significance (2 clinical laboratories, single submitter each).	clinvar
BP7	N/A	BP7 is specific to synonymous variants with no predicted splice impact. NM_005235.2:c.2371A>G is a missense variant (p.Thr791Ala) and does not qualify for BP7 assessment.
BP3	N/A	Skipped: variant is a substitution, not an in-frame indel in a repetitive region.
PM3	N/A	Skipped: no recessive disease has been firmly linked to biallelic ERBB4 mutations, and no trans observation with a pathogenic variant has been reported.
PM4	N/A	Skipped: variant is a substitution, not a protein-length-altering change (in-frame deletion/insertion or stop-loss).

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