NM_001023.4:c.24A>G

RPS20 · NP_001014.1:p.(Lys8=) · NM_001023.4

GRCh37: chr8:56986698 T>C · GRCh38: chr8:56074139 T>C

Gene: RPS20 Transcript: NM_001023.4

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

RPS20

Transcript

NM_001023.4

Protein

NP_001014.1:p.(Lys8=)

gnomAD AF

6.198882465469126e-07 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001023.4:c.24A>G (p.Lys8=) is a synonymous variant in exon 2 of RPS20 with no predicted effect on splicing (SpliceAI max delta = 0.00).

This variant has been classified as Likely benign in ClinVar by a single clinical laboratory (Ambry Genetics, criteria provided; variation ID 2488528).

The variant is present at extremely low frequency in population databases (gnomAD v2.1: 1/249,106 alleles, AF = 0.0004%; v4.1: 1/1,613,194 alleles, AF = 0.00006%), but rarity alone does not confer pathogenicity for a synonymous change with no functional consequence.

No functional studies, case-control data, de novo reports, segregation data, or publications mentioning this specific variant were identified.

Three supporting benign criteria are met: BP4 (computational evidence predicts no impact), BP6 (reputable source reports as benign), and BP7 (synonymous variant with no splice effect). This is consistent with a Likely benign classification per ACMG/AMP 2015 guidelines.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting 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 is a synonymous variant (NP_001014.1:p.(Lys8=)). PVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2, initiation codon, single/multi-exon deletion); a silent substitution does not qualify.	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at c.24 resulting in the same amino acid (p.Lys8=) has been reported as pathogenic. This is a synonymous variant; there is no known pathogenic comparator with the same protein consequence.	clinvar
PS2	Not assessed	No de novo data are available. No publications or clinical reports for this variant include de novo confirmation with parental testing.
PS3	Not met	No functional studies have been identified for this variant. No variant-specific or systematic range characterization (tiling screen, saturation mutagenesis, truncation series) includes NM_001023.4:c.24A>G.
PS4	Not assessed	No case-control or cohort data comparing variant prevalence in affected versus unaffected individuals are available.
PS5	Not assessed	No data available to assess this criterion. No validated functional assay or established pathogenic comparator at the same position has been identified for this synonymous variant.
PM1	Not met	This variant is not located in a statistically significant mutational hotspot (cancerhotspots.org negative), and as a synonymous variant (p.Lys8=) it does not alter any amino acid residue in a critical functional domain.
PM2	Met	This variant is present at an extremely low frequency in population databases: gnomAD v2.1 AF = 4.01e-6 (1/249,106 alleles) and v4.1 AF = 6.20e-7 (1/1,613,194 alleles), well below the 0.1% PM2 threshold. However, this is a synonymous variant with no other evidence of pathogenicity, limiting the weight of rarity alone.	gnomad_v2 gnomad_v4
PM5	N/A	This is a synonymous variant (p.Lys8=), not a missense change. PM5 requires a different missense variant at the same residue previously classified as pathogenic.
PM6	Not assessed	No de novo data are available. No publications report de novo occurrence of this variant with confirmed maternity and paternity.
PP1	Not assessed	No co-segregation data are available. No family studies have been reported for this variant.
PP2	N/A	This is a synonymous variant, not a missense change. PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	No in silico predictors suggest a deleterious effect. REVEL and BayesDel scores are unavailable for this synonymous variant. SpliceAI predicts no splice impact (max delta = 0.00). No computational evidence supports pathogenicity.	spliceai
PP4	Not assessed	No patient phenotype or clinical data are available to assess whether the presentation is highly specific for an RPS20-related disorder.
PP5	Not met	ClinVar classifies this variant as Likely benign, not pathogenic. No reputable source has reported it as pathogenic.	clinvar
BA1	Not met	The maximum allele frequency in gnomAD is 4.01e-6 (0.0004%), far below the 1% BA1 threshold. This variant is not a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency in gnomAD is 4.01e-6 (0.0004%), well below the 0.3% BS1 threshold. Population frequency does not support a benign classification via BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults with full penetrance expected at their age.
BS3	Not assessed	No well-established functional studies have evaluated this variant for a deleterious effect. No functional data are available.
BS4	Not assessed	No segregation data are available to assess lack of co-segregation with disease.
BP1	N/A	This is a synonymous variant, not a missense change. BP1 applies only to missense variants in genes where primarily truncating variants cause disease.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP4	Met	SpliceAI predicts no splice impact for this variant (max delta score = 0.00). The variant is synonymous (p.Lys8=) and is predicted not to alter splicing or protein sequence. Multiple lines of computational evidence are consistent with no functional impact.	spliceai
BP5	Not assessed	No data are available regarding an alternative molecular basis for disease in a case harboring this variant.
BP6	Met	This variant has been reported in ClinVar as Likely benign by Ambry Genetics, a clinical testing laboratory, with criteria provided. Although from a single submitter, the classification supports a benign interpretation in the absence of any pathogenic evidence.	clinvar
BP7	Met	This is a synonymous variant (p.Lys8=) with no predicted splice impact (SpliceAI max delta = 0.00). BP7 is met for a silent variant with no evidence of altered splicing.	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.