0%
SF3B1c.1873C>AUncertain significance
Print report
Variant interpretation report

SF3B1 c.1873C>A, p.(Arg625Ser)

NM_012433.3:c.1873C>A NP_036565.2:p.(Arg625Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About SF3B1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate

The variant alters residue Arg625, which lies in a statistically significant mutational hotspot in SF3B1. SF3B1 hotspot mutations cluster in the HEAT domain, and codon 625 is a well-established recurrent mutation site.

PM2Moderate
PM2 · moderate

This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.2e-07 (1/1,613,940 alleles, 0 homozygotes), with the single observation in the South Asian subpopulation (AF 1.1e-05). This frequency is well below the 0.1% PM2 threshold for non-VCEP assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate; combination = 2 moderate, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.120 maximum delta

Recorded SpliceAI maximum delta score: 0.120. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SF3B1, a component of the spliceosome complex, is frequently mutated in hematologic malignancies.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV59228873, n = 3 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 6 not met · 12 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The variant c.1873C>A (p.Arg625Ser) in SF3B1 alters a residue in a statistically significant mutational hotspot, meeting PM1 at moderate strength.

The variant is extremely rare in population databases, present at an allele frequency of 6.2e-07 (1/1,613,940 alleles) in gnomAD v4.1 and absent from gnomAD v2.1, meeting PM2 at moderate strength.

Computational evidence is discordant: REVEL predicts a deleterious effect (0.806) but BayesDel predicts a benign effect (0.235), and SpliceAI predicts no splicing impact (delta 0.12). PP3 and BP4 are not met.

No variant-specific publications, ClinVar classifications, de novo reports, functional studies, or segregation data are available. Multiple criteria (PS2, PS3, PS4, PM6, PP1, PP4, BS2, BS3, BS4, BP2, BP5) could not be assessed.

The variant is absent from ClinVar and has not been classified by any germline reputable source; PP5 and BP6 are not met.

Two moderate pathogenic criteria (PM1, PM2) are met with zero benign criteria met. This falls short of the Likely Pathogenic threshold (≥3 moderate, or ≥2 moderate + ≥2 supporting, or ≥1 strong + ≥1 moderate) per ACMG/AMP 2015 combination rules. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM1 ModerateThe variant alters residue Arg625, which lies in a statistically significant mutational hotspot in SF3B1. SF3B1 hotspot mutations cluster in the HEAT domain, and codon 625 is a well-established recurrent mutation site. Details ▾Hide ▴
Evidence considered
  • CancerHotspots: residue R625 is in a statistically significant mutational hotspot (residue_significant: true).
PM2 ModerateThis variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.2e-07 (1/1,613,940 alleles, 0 homozygotes), with the single observation in the South Asian subpopulation (AF 1.1e-05). This frequency is well below the 0.1% PM2 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF 6.2e-07 (1/1
  • 613
  • 940 alleles
  • 0 homozygotes). gnomAD v2.1: absent.
Sources
gnomad_v4 ↗gnomad_v2 ↗

Not met · 6 · evaluated, threshold not reached

PP3 Multiple lines of computational evidence do not consistently support a deleterious effect. REVEL score of 0.806 supports pathogenicity (above 0.75 threshold), but BayesDel score of 0.235 is discordant and supports a benign interpretation. SpliceAI delta score of 0.12 predicts no significant splice impact. Only one of three in silico tools supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.806 (pathogenic-leaning). BayesDel: 0.235 (benign-leaning). SpliceAI: max delta 0.12 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP5 This variant is absent from ClinVar and has not been classified by any reputable source. OncoKB classifies it as 'Likely Oncogenic,' but this is a somatic designation and does not satisfy PP5 requirements for a germline source. Details ▾Hide ▴
Evidence considered
  • ClinVar: absent (no classification). OncoKB: Likely Oncogenic (somatic context
  • not germline PP5-eligible).
Sources
clinvar ↗oncokb ↗
BA1 The allele frequency of this variant in gnomAD v4.1 is 6.2e-07 (0.000062%), which is far below the 1% BA1 threshold. This variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF 6.2e-07
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 The allele frequency of this variant in gnomAD v4.1 is 6.2e-07 (0.000062%), which is far below the 0.3% BS1 threshold for non-VCEP assessment. The variant is extremely rare in the general population. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF 6.2e-07
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BP4 Multiple lines of computational evidence do not consistently suggest no impact on the gene product. REVEL score of 0.806 supports a deleterious effect, contradicting a benign prediction. BayesDel score of 0.235 is in the benign range, but SpliceAI delta score of 0.12 is uninformative. The evidence does not meet the threshold for multiple lines all pointing to no impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.806 (deleterious). BayesDel: 0.235 (benign-leaning). SpliceAI: 0.12 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP6 This variant is absent from ClinVar; no reputable source has reported it as benign. BP6 requires a reputable source to classify the variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: absent
  • no benign classification from any source.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS2 No de novo reports with confirmed maternity and paternity are available for this variant. No publications were identified in the literature pass. Details ▾Hide ▴
Still missing
  • No publications or clinical reports available for de novo assessment.
PS3 No variant-specific well-established functional studies are available. OncoKB classifies this variant as 'Likely Oncogenic' in a somatic context and COSMIC reports three somatic occurrences (COSV59228873), but no publications with experimental functional evidence were identified for independent verification. Details ▾Hide ▴
Evidence considered
  • OncoKB: Likely Oncogenic (no supporting PMIDs). COSMIC: 3 somatic samples (COSV59228873).
Still missing
  • No publications with variant-specific functional assays available for review.
Sources
oncokb ↗
PS4 No case-control or variant prevalence data in affected versus unaffected individuals are available. The variant is absent from ClinVar and no publications with patient counts were identified. Details ▾Hide ▴
Still missing
  • No affected vs. control prevalence data available.
PM6 No de novo reports (confirmed or unconfirmed parentage) are available for this variant. No publications were identified in the literature pass. Details ▾Hide ▴
Still missing
  • No publications or clinical reports available for de novo assessment.
PP1 No co-segregation data in affected families is available for this variant. No publications with family studies were identified. Details ▾Hide ▴
Still missing
  • No family co-segregation data available.
PP2 SF3B1 is a gene where missense variants are a known disease mechanism (germline de novo missense variants cause neurodevelopmental disorders per PMID:41577671). However, insufficient data on the gene's benign missense variation rate (e.g., missense Z-score or constraint metrics) are available to formally apply PP2. Details ▾Hide ▴
Evidence considered
  • SF3B1 missense variants are a known disease mechanism
  • but missense constraint data are unavailable.
Still missing
  • No gnomAD missense Z-score or regional constraint data available in evidence brief.
PP4 No patient phenotype or clinical data are available for this variant. The variant is absent from ClinVar and no case reports were identified. Details ▾Hide ▴
Still missing
  • No clinical phenotype data available.
BS2 No data on observation of this variant in healthy adult controls are available. The single gnomAD v4.1 observation lacks phenotypic annotation. Details ▾Hide ▴
Still missing
  • No healthy adult control phenotype data available for the single gnomAD carrier.
BS3 No variant-specific well-established functional studies demonstrating a benign effect are available. No publications were identified in the literature pass. Details ▾Hide ▴
Still missing
  • No publications with variant-specific functional assays available.
BS4 No family segregation data are available to evaluate lack of segregation with disease. No publications with family studies were identified. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP2 No data on observation of this variant in trans with a pathogenic variant are available. The variant has not been reported in any clinical or research context. Details ▾Hide ▴
Still missing
  • No trans phase data available.
BP5 No data are available on cases harboring this variant with an alternate molecular basis for disease. No publications or clinical reports were identified. Details ▾Hide ▴
Still missing
  • No case data with alternate molecular diagnoses available.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.1873C>A, p.Arg625Ser) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 variant assessment confirms this variant is not eligible for generic PVS1 framework application. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 625
  • not a predicted null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo known pathogenic variant with the same amino acid change (Arg625Ser) has been identified. This variant is absent from ClinVar, and no same-residue pathogenic comparators were found. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid pathogenic variant exists for PS1 comparison.
Sources
clinvar ↗pm5_candidates
PM3 N/ASF3B1-associated disorders follow autosomal dominant inheritance with de novo heterozygous variants; PM3 is for recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a missense substitution; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo pathogenic missense comparator at the same residue (Arg625) was identified. PM5 candidate harvesting found zero same-residue candidates, and ClinVar lacks entries at this position. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review found zero same-residue pathogenic comparators.
Sources
pm5_candidatesclinvar ↗
BP1 N/ASF3B1 missense variants are a known disease mechanism; germline de novo missense variants cause neurodevelopmental disorders (PMID:41577671). BP1 is reserved for genes where primarily truncating variants cause disease, which is not the case for SF3B1. Details ▾Hide ▴
Evidence considered
  • SF3B1 de novo missense variants are associated with neurodevelopmental disorders (PMID:41577671)
  • missense is an established disease mechanism.
Sources
pvs1_gene_context
BP3 N/AThis is a substitution variant; BP3 applies to in-frame insertions/deletions in repetitive regions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.1873C>A, p.Arg625Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criterion is reserved for synonymous variants.
PS5 N/ANo alternate pathogenic missense variant at the same residue (Arg625) has been identified in ClinVar or other sources. PM5 candidate harvesting found no same-residue comparators. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review found no alternate pathogenic missense at Arg625.
Sources
pm5_candidatesclinvar ↗

Identifiers

Gene
SF3B1
Transcript
NM_012433.3
Coding (HGVS c.)
NM_012433.3:c.1873C>A
Protein (HGVS p.)
NP_036565.2:p.(Arg625Ser)
GRCh38
chr2:197402760 G>T
GRCh37
chr2:198267484 G>T
COSMIC
COSV59228873

Gene diagram

Every interpreted variant in SF3B1, mapped onto the exon structure of NM_012433.3. Select a row to find it on the plot.

SF3B1NM_012433.3
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,613,940 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,940 alleles · 0 hom
South Asian1 / 91,060 1.1e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19602e-07; MAF= 0.00006%, 1/1613940 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09818e-05; MAF= 0.00110%, 1/91060 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +66 bp
0.000
SpliceAI acceptor gainat -247 bp
0.010
SpliceAI donor lossat -117 bp
0.020
SpliceAI donor gainat +4 bp
0.120
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.020

Other predictors

REVEL
0.806
BayesDel
0.235

How the predictions were used

PP3 Multiple lines of computational evidence do not consistently support a deleterious effect. REVEL score of 0.806 supports pathogenicity (above 0.75 threshold), but BayesDel score of 0.235 is discordant and supports a benign interpretation. SpliceAI delta score of 0.12 predicts no significant splice impact. Only one of three in silico tools supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.806 (pathogenic-leaning). BayesDel: 0.235 (benign-leaning). SpliceAI: max delta 0.12 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP4 Multiple lines of computational evidence do not consistently suggest no impact on the gene product. REVEL score of 0.806 supports a deleterious effect, contradicting a benign prediction. BayesDel score of 0.235 is in the benign range, but SpliceAI delta score of 0.12 is uninformative. The evidence does not meet the threshold for multiple lines all pointing to no impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.806 (deleterious). BayesDel: 0.235 (benign-leaning). SpliceAI: 0.12 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.1873C>A, p.Arg625Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criterion is reserved for synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.806. BayesDel score = 0.235333.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,613,940 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.120 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19602e-07; MAF= 0.00006%, 1/1613940 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09818e-05; MAF= 0.00110%, 1/91060 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.806. BayesDel score = 0.235333.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SF3B1, a component of the spliceosome complex, is frequently mutated in hematologic malignancies.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59228873, n = 3 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.