Variant classification summary

NM_003016.4:c.284C>A

SRSF2 · NP_003007.2:p.(Pro95His) · NM_003016.4

GRCh37: chr17:74732959 G>T · GRCh38: chr17:76736877 G>T

Gene: SRSF2 Transcript: NM_003016.4

Final call

VUS

PS3 strong PM2 supporting BP5 supporting

Variant details

Gene

SRSF2

Transcript

NM_003016.4

Protein

NP_003007.2:p.(Pro95His)

gnomAD AF

9.746612896817513e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 strong supports altered SRSF2 splicing, RNA binding, and hematopoietic function.

2

Pathogenic evidence: PM2 supporting reflects an extremely low gnomAD v4.1 allele frequency with zero homozygotes.

3

Benign-direction evidence: BP5 supporting identifies an alternate molecular basis in the reported case.

4

VUS: these applied criteria satisfy neither a generic pathogenic nor benign combination rule.

Final determination: Under generic ACMG/AMP 2015 rules, PS3 Strong with PM2 Supporting does not reach a pathogenic or likely pathogenic combination, and BP5 Supporting alone does not reach a benign or likely benign combination; therefore the call is 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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no independent previously established pathogenic variant with the same SRSF2 Pro95His amino-acid change but a different nucleotide change was identified.	clinvar
PS2	Not assessed	Not assessed: no documented germline proband with confirmed maternity and paternity, disease phenotype, and absence of family history is available.	PMID:26261309
PS3	Met	Met, strong: P95H caused 548 misregulated splicing events in CRISPR knock-in cells and concordant RNA-binding, cellular, and in vivo hematopoietic abnormalities across four studies.	PMID:25965569 PMID:26124281 PMID:26261309 PMID:27135740 PMID:31040863
PS4	Not assessed	Not assessed: affected cases were reported, but no valid exact-variant case-control odds ratio and confidence interval were available for comparison with the >5.0 PS4 threshold.	PMID:21909114 gnomad_v4
PM1	Not assessed	Not assessed: P95 is a statistically significant recurrent hotspot, but evidence that the hotspot lacks benign variation is not available.	PMID:21909114 hotspots
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 0.00009783, just below the 0.0001 PM2 threshold, with zero homozygotes.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: No parent or offspring phase data document NM_003016.4:c.284C>A in trans with a pathogenic variant in an affected proband.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: P95L and P95R are reported at residue 95, but neither is established as pathogenic by the available evidence.	PMID:31040863
PM6	Not assessed	Not assessed: no proband-level assumed de novo report with the relevant parental-testing and family-history context is available.	PMID:26261309
PP1	Not assessed	Not assessed: zero informative affected relatives or documented co-segregating meioses are available for this variant.	PMID:26261309
PP2	Not assessed	Not assessed: recurrent somatic SRSF2 missense mutations are shown, but low benign missense variation and a common disease missense mechanism are not both established.	PMID:21909114 gnomad_v4
PP3	Not met	Not met: REVEL 0.419 is below the generic PP3 supporting threshold of >= 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no sufficiently specific patient phenotype or family history was available to establish a single-genetic-etiology disease under PP4.
PP5	Not met	Not met: ClinVar lists one exact-variant Pathogenic laboratory submission, but no expert-panel classification supports PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00009783, far below the 0.05 stand-alone BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest applicable filtering FAF is 0.00013143, well below the generic 0.01 BS1 default.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no established germline inheritance, penetrance, or early-onset full-penetrance model supports interpreting database controls under BS2.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: no benign functional result was reported, while P95H produced 548 altered splicing events and concordant RNA-binding and hematopoietic abnormalities.	PMID:25965569 PMID:26124281 PMID:26261309 PMID:27135740 PMID:31040863
BS4	Not assessed	Not assessed: no affected relatives with documented negative variant testing are available to demonstrate lack of segregation.	PMID:26261309
BP1	Not assessed	Not assessed: no evidence establishes that SRSF2 disease is caused primarily by truncating variants rather than missense variants.	PMID:21909114
BP2	Not assessed	Not assessed: No phase or affected-proband allele-pair data show the variant in trans or cis with a pathogenic variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.419 exceeds the generic BP4 supporting threshold of <= 0.29 for this missense variant.	revel
BP5	Met	Met, supporting: the exact variant occurred with homozygous JAK2 V617F and ASXL1 c.1720-2A>G, providing an alternate molecular basis for the reported disease progression.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification was identified for BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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