NM_198253.2:c.1950+10C>T

TERT · NP_937983.2:p.? · NM_198253.2

GRCh37: chr5:1280263 G>A · GRCh38: chr5:1280148 G>A

Gene: TERT Transcript: NM_198253.2

Final call

Benign

BA1 stand-alone benign BP4 supporting

Variant details

Gene

TERT

Transcript

NM_198253.2

Protein

NP_937983.2:p.?

gnomAD AF

0.012166515904387802 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The TERT c.1950+10C>T (p.?) variant has been reported in ClinVar as Benign by 14 clinical laboratories.

This variant is common in population databases, with allele frequencies of 1.36750% in gnomAD v2.1 and 1.21665% in gnomAD v4.1, both above the 1% BA1 threshold, and reaches approximately 4.14% to 4.07% in the Finnish population.

In silico splice prediction does not support a clinically meaningful splicing effect, with SpliceAI showing a maximum delta score of 0.07.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	This intronic c.1950+10C>T variant is outside the canonical +/-1,2 splice positions and does not fall into the generic null-variant categories used for default PVS1 application, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	This is not a protein-coding substitution with an established amino acid change, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo data with verified parentage were identified for this variant.
PS3	Not assessed	No validated functional study of this exact variant showing a damaging effect was identified.
PS4	Not met	Available evidence does not show that this variant is enriched in affected individuals compared with controls.	clinvar
PM1	N/A	This intronic +10 variant is not located in a defined mutational hotspot or critical functional domain established for PM1 use.
PM2	Not met	This variant is not absent from population databases; instead, it is common in gnomAD with total allele frequencies of 1.36750% in v2.1 and 1.21665% in v4.1, which is far above the generic PM2 rarity threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease setting.
PM4	N/A	This intronic substitution does not produce a protein length change, so PM4 is not applicable.
PM5	N/A	This variant does not have a defined missense residue context, and the PM5 review artifact did not support classic same-residue PM5 use, so PM5 is not applicable.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	This is not a missense variant, so PP2 is not applicable.
PP3	Not met	Available computational evidence does not support a damaging effect on splicing. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.07, which is below commonly used concern thresholds.	spliceai
PP4	Not assessed	No phenotype data specific enough to support a highly characteristic TERT-related presentation for this variant were identified.
PP5	Not assessed	PP5 was not used because primary supporting evidence for a pathogenic classification was not identified, and this criterion is not relied on here.
BA1	Met	Population frequency exceeds the generic BA1 threshold of 1%. This variant is present at 1.36750% in gnomAD v2.1 and 1.21665% in gnomAD v4.1, with the highest observed frequency in the Finnish population at about 4.14% and 4.07%, respectively, which strongly supports a benign interpretation.	gnomad_v2 gnomad_v4
BS1	N/A	Although the observed population frequency is also above the generic BS1 threshold of 0.3%, BA1 is already met at a stronger benign level, so BS1 is not separately applied to avoid double counting the same frequency evidence.	gnomad_v2 gnomad_v4
BS2	Not assessed	Although this variant is observed many times in population databases, no dataset-specific healthy adult phenotyping framework was identified to support independent BS2 application.	gnomad_v2 gnomad_v4
BS3	Not assessed	No validated functional study of this exact variant showing a normal or no-impact effect was identified.
BS4	Not assessed	No family data were identified showing lack of segregation with disease.
BP1	N/A	This is not a missense variant, so BP1 is not applicable.
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP3	N/A	This intronic variant is not located in a repetitive region or described low-complexity region used for BP3 assessment.
BP4	Met	Available computational evidence supports no meaningful impact on splicing. SpliceAI predicts no significant splice effect, with a maximum delta score of 0.07, which is below commonly used thresholds for splice disruption.	spliceai
BP5	Not assessed	No independent alternate molecular explanation for a reported phenotype was identified.
BP6	Not assessed	Although ClinVar contains multiple benign submissions, BP6 was not separately applied because the benign classification itself is not treated here as independent criterion-level evidence beyond the underlying population and computational findings.	clinvar
BP7	N/A	This is not a synonymous or deep intronic silent variant assessed under BP7 wording; instead, the relevant noncoding computational evidence was considered under BP4.	spliceai

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.