Variant classification summary

NM_003016.4:c.283C>A

SRSF2 · NP_003007.2:p.(Pro95Thr) · NM_003016.4

GRCh37: chr17:74732960 G>T · GRCh38: chr17:76736878 G>T

Gene: SRSF2 Transcript: NM_003016.4

Final call

VUS

PM1 moderate PM2 supporting BP4 supporting

Variant details

Gene

SRSF2

Transcript

NM_003016.4

Protein

NP_003007.2:p.(Pro95Thr)

gnomAD AF

6.826463842082791e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (moderate): Pro95 is located within the RRM domain of SRSF2, a well-established functional domain and mutational hotspot where other pathogenic missense changes (P95H, P95L, P95R) have been documented in COSMIC. Cancer Hotspots confirms the residue as statistically significant.

2

PM2 (supporting): This variant is present at extremely low frequency in gnomAD (v2.1: 2/239,628 alleles, AF=8.35e-06; v4.1: 11/1,611,376 alleles, AF=6.83e-06), well below the 0.1% PM2 threshold. No homozygotes observed. Absent from gnomAD-Canada.

3

BP4 (supporting): Multiple lines of computational evidence suggest no significant impact: REVEL score 0.444, BayesDel score -0.15213 (benign), and SpliceAI max delta score 0.00 (no predicted splicing effect).

4

Overall assessment: 1 moderate pathogenic criterion (PM1) + 1 supporting pathogenic criterion (PM2) + 1 supporting benign criterion (BP4). Using generic ACMG/AMP 2015 combination rules (PMID:25741868), this combination of criteria is insufficient to reach Likely Pathogenic (requires ≥2 moderate or 1 moderate + ≥4 supporting), Likely Benign (requires ≥1 strong benign + 1 supporting benign, or ≥2 supporting benign), or Benign. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	NM_003016.4:c.283C>A is a missense variant (p.Pro95Thr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework per ClinGen SVI recommendations (PMC6185798) does not apply to missense changes.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No other nucleotide change producing the same amino acid substitution (p.Pro95Thr) has been reported as pathogenic. The known pathogenic changes at codon 95 (c.284C>A/p.Pro95His; c.284C>T/p.Pro95Leu; c.284C>G/p.Pro95Arg) produce different amino acid substitutions.
PS2	Not met	No reports of de novo occurrence of SRSF2 p.Pro95Thr in a patient with a matching phenotype and confirmed parentage were identified in the literature or databases.
PS3	Not met	No well-established in vitro or in vivo functional studies specifically assessing the functional impact of p.Pro95Thr were identified. Published functional studies of SRSF2 codon 95 variants focus on the more common P95H, P95L, and P95R substitutions (PMID:25687329, PMC7410493) and do not include data on P95T.
PS4	Not met	No case-control studies demonstrating statistically significant enrichment of p.Pro95Thr in affected individuals versus controls were identified. The variant is extremely rare in gnomAD but no affected cohort frequency data are available for comparison.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion (Richards et al., PMID:25741868). In the generic ACMG/AMP framework, this concept is subsumed by PM5 (novel missense at residue with known pathogenic missense). Assessed under PM5 instead.	generic_acmg_combination_rules
PM1	Met	Pro95 is located within the RNA recognition motif (RRM) domain of SRSF2, a well-established functional domain critical for RNA binding and splicing. This codon is a known mutational hotspot in hematologic malignancies, with recurrent pathogenic missense changes (P95H, P95L, P95R) documented in COSMIC. Cancer Hotspots analysis confirms the residue is statistically significant.	oncokb
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 exomes AF=8.35e-06 (2/239,628 alleles, 0 homozygotes) and gnomAD v4.1 AF=6.83e-06 (11/1,611,376 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4
PM5	Not met	While other missense changes at Pro95 (P95H, P95L, P95R) are well-established somatic driver mutations in hematologic malignancies, no germline pathogenic or likely pathogenic classification exists in ClinVar for a different missense substitution at this residue. PM5 requires a different missense change at the same residue with an established pathogenic classification, which is not met in the germline context.	pm5_candidates
PM6	Not met	No reports of presumed de novo occurrence (without confirmation of parentage) were identified for this variant.
PP1	Not met	No family segregation data are available for this variant. SRSF2 germline mutations are not commonly associated with inherited syndromes for which segregation studies have been performed.
PP2	Not assessed	Insufficient data to determine whether SRSF2 has a low rate of benign missense variation (e.g., high missense Z-score from gnomAD constraint metrics). PP2 cannot be applied without gene-level missense constraint metrics.
PP3	Not met	Multiple in silico predictors do not support a damaging effect: REVEL score 0.444 (below the typical pathogenic threshold of 0.5), BayesDel score -0.152 (negative score indicates benign), and SpliceAI predicts no splicing impact (max delta score 0.00).	revel bayesdel spliceai
PP4	Not assessed	No specific patient phenotype or clinical information was provided with this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical context.
PP5	Not met	This variant is absent from ClinVar. No reputable source (clinical laboratory, expert panel) has reported this variant as pathogenic.	clinvar
BA1	Not met	The allele frequency in gnomAD is far below the 1% BA1 threshold: v2.1 AF=0.00083%, v4.1 AF=0.00068%.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD is below the 0.3% BS1 threshold: v2.1 AF=0.00083%, v4.1 AF=0.00068%.	gnomad_v2 gnomad_v4
BS2	N/A	SRSF2 is not associated with a well-established Mendelian disorder with full penetrance at an early age. BS2 requires observation in a healthy adult individual for a disorder where full penetrance is expected early in life. Without a clearly defined SRSF2 germline disease with known penetrance, BS2 cannot be properly applied.	pvs1_gene_context
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate that p.Pro95Thr has no damaging effect on protein function or splicing. Published functional studies on Pro95 mutations (P95H, P95L, P95R) show altered function, but p.Pro95Thr has not been specifically tested.
BS4	Not met	No family studies are available to assess lack of segregation of this variant with disease in affected family members.
BP1	N/A	SRSF2-related disease is driven primarily by missense variants, not truncating variants. BP1 applies when a gene's disease mechanism is primarily through truncating variants and the variant in question is missense.	pvs1_gene_context
BP2	N/A	SRSF2 is not established as a Mendelian disease gene with clearly defined dominant or recessive inheritance. BP2 requires observation in trans with a pathogenic variant in a gene with established recessive inheritance, or in cis with a pathogenic variant in a dominant disorder. Neither context is applicable here.	pvs1_gene_context
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product: REVEL score 0.444 (below pathogenic threshold), BayesDel score -0.15213 (predicts benign), and SpliceAI predicts no splicing alteration (max delta score 0.00).	revel bayesdel spliceai
BP5	Not met	No evidence is available that this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not met	This variant is absent from ClinVar. No reputable source has reported this variant as benign without the evidence being available for independent evaluation.	clinvar
BP7	N/A	NM_003016.4:c.283C>A is a missense variant (p.Pro95Thr), not a synonymous or intronic variant. BP7 applies only to synonymous variants predicted not to affect splicing.

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