Variant classification summary

NM_198253.2:c.1812A>G

TERT · NP_937983.2:p.(Ala604=) · NM_198253.2

GRCh37: chr5:1280411 T>C · GRCh38: chr5:1280296 T>C

Gene: TERT Transcript: NM_198253.2

Final call

VUS

BP7 supporting

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.(Ala604=)

gnomAD AF

0.0033687936669653715 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP7 (Supporting): synonymous variant with SpliceAI max delta 0.034, below the 0.1 threshold, indicating no predicted splice disruption.

2

Overall classification: VUS - with only BP7 (supporting) applied under the generic ACMG/AMP 2015 fallback, the variant is of uncertain significance.

Final determination: 1 BP supporting alone does not meet any combination threshold, so VUS.

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	Not applicable: this synonymous change (p.Ala604=) triggers no null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no amino acid change exists (p.Ala604=) to compare against a previously established pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with parental testing was documented.
PS3	Not assessed	Not assessed: no functional assay data for this specific variant were available.
PS4	Not assessed	Not assessed: no case-control or prevalence evidence for this exact variant was available.
PM1	N/A	Not applicable: no altered residue exists to evaluate for hotspot or critical-domain membership (p.Ala604=).	generic_acmg_combination_rules
PM2	Not met	Not met: present in gnomAD v4.1 at 0.34% overall frequency, so not absent from population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observations, second allele, phase, or inheritance data were available.	generic_acmg_combination_rules
PM4	N/A	Not applicable: no protein length change occurs (synonymous, p.Ala604=).	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a known pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no evidence of an assumed de novo occurrence without parental testing was available.
PP1	Not assessed	Not assessed: no informative segregation data or pedigree were available.
PP2	N/A	Not applicable: no missense change is present to evaluate (synonymous, p.Ala604=).	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.034, far below the 0.2 threshold for predicted splice impact.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient-level phenotype data linked to this exact variant were available.
PP5	Not met	Not met: ClinVar labels are Benign/Likely benign from single submitters, with no expert-panel classification.	clinvar
BA1	Not met	Not met: highest population frequency is 0.63%, far below the >5% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not assessed	Not assessed: no disorder-specific prevalence or maximum credible allele-frequency threshold to compare against the observed 0.34% frequency.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS2	Not assessed	Not assessed: homozygotes (10 in gnomAD v4.1) lack phenotype, age, and follow-up confirming healthy status.	gnomad_v4 gnomad_canada PMID:25741868
BS3	Not assessed	Not assessed: no functional assay demonstrating normal activity was available for this variant.
BS4	Not assessed	Not assessed: no unaffected relatives documented as carrying the variant with phenotype evaluation.
BP1	N/A	Not applicable: no missense change is present to evaluate (synonymous, p.Ala604=).	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no observation of this variant in cis or in trans with a pathogenic variant.	generic_acmg_combination_rules
BP3	N/A	Not applicable: no in-frame insertion/deletion or protein length change occurs (synonymous).	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the benign splice prediction is credited under BP7, and no missense score exists for this synonymous variant.	spliceai
BP5	Not assessed	Not assessed: no evidence that the phenotype is explained by an alternative molecular cause.
BP6	Not met	Not met: ClinVar benign submissions come from single submitters, with no expert-panel classification.	clinvar
BP7	Met	Met (Supporting): SpliceAI max delta 0.034, below the 0.1 threshold, indicating no predicted splice disruption.	spliceai generic_acmg_combination_rules

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