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SF3B1c.1876A>GUncertain significance
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Variant interpretation report

SF3B1 c.1876A>G, p.(Asn626Asp)

NM_012433.2:c.1876A>G NP_036565.2:p.(Asn626Asp) 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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Population frequency is below the non-VCEP PM2 threshold of 0.1% in gnomAD v2.1 (0.00040%, 1/251158 alleles) and gnomAD v4.1 (0.00050%, 8/1613994 alleles; grpmax FAF 0.000124%), supporting rarity in population databases.

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: PM2 supporting; combination = 1 supporting, 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.

gnomAD v4.1
gnomAD v2.1
Population frequency
8 / 1,613,994 alleles

gnomAD v4.1: 8 / 1,613,994 alleles. Recorded AF 4.95665e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98156e-06; MAF= 0.00040%, 1/251158 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89385e-05; MAF= 0.00289%, 1/34556 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 1 met · 4 not met · 19 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The SF3B1 c.1876A>G (p.Asn626Asp; p.N626D) variant has been curated as a somatic cancer variant in OncoKB and has not been reported in ClinVar.

This variant is rare in population databases, with gnomAD v2.1 showing 1/251158 alleles (0.00040%) and gnomAD v4.1 showing 8/1613994 alleles (0.00050%; grpmax FAF 0.000124%), which is below the 0.1% PM2 threshold.

In silico results are mixed: SpliceAI predicts no significant splice impact (maximum delta score 0.08), while REVEL is 0.60 and BayesDel is -0.0733292, so computational evidence does not independently support PP3 or BP4.

Met · 1

PM2 SupportingPopulation frequency is below the non-VCEP PM2 threshold of 0.1% in gnomAD v2.1 (0.00040%, 1/251158 alleles) and gnomAD v4.1 (0.00050%, 8/1613994 alleles; grpmax FAF 0.000124%), supporting rarity in population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 3.98156e-06
  • gnomAD v4.1 AF 4.95665e-06
  • gnomAD v4.1 grpmax FAF 1.24e-06
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PP3 Computational evidence is mixed. REVEL is 0.60, BayesDel is -0.0733292, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, so in silico results do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.60
  • BayesDel -0.0733292
  • SpliceAI max delta 0.08
Still missing
  • No concordant computational signal was present across available predictors
Sources
revelbayesdelspliceai ↗
BA1 Population frequency does not meet the benign stand-alone BA1 threshold of greater than 1%. The highest observed gnomAD v4.1 population frequency is 0.00320% and overall frequency is 0.00050%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 overall AF 4.95665e-06
  • gnomAD v4.1 highest population AF 3.20092e-05
  • gnomAD v2.1 overall AF 3.98156e-06
Sources
gnomad_v4 ↗gnomad_v2 ↗
BS1 Population frequency does not meet the benign BS1 threshold of greater than 0.3%. The highest observed gnomAD v4.1 population frequency is 0.00320%, which is well below this threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 highest population AF 3.20092e-05
  • gnomAD v2.1 highest population AF 2.89385e-05
Sources
gnomad_v4 ↗gnomad_v2 ↗
BP4 Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact (max delta 0.08), but REVEL is 0.60 and BayesDel is -0.0733292, so the overall in silico profile is mixed. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08
  • REVEL 0.60
  • BayesDel -0.0733292
Still missing
  • No concordant benign computational signal was present across available predictors
Sources
spliceai ↗revelbayesdel

Not assessed · 19 · no assessment recorded

PS1 No evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic interpretation. Details ▾Hide ▴
Still missing
  • No same-codon alternate nucleotide comparison was identified
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified. Details ▾Hide ▴
Evidence considered
  • ClinVar search was negative for this variant
Still missing
  • No trio-based case report was identified
  • No de novo annotation was found in the available clinical database review
Sources
clinvar ↗
PS3 No published functional study specific to p.(Asn626Asp) was identified that demonstrates a damaging effect using a validated assay. Details ▾Hide ▴
Evidence considered
  • OncoKB flagged variant-specific curated literature context but no PMID-backed functional result was captured in the reviewed materials
Still missing
  • No exact-variant functional assay result was retrieved
Sources
oncokb ↗
PS4 Somatic database curation suggests this variant has been observed in cancers, but no germline case-control or affected-versus-control enrichment data were identified for this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB returned a variant-specific somatic entry
  • ClinVar had no germline submission for this variant
Still missing
  • No germline enrichment study was identified
  • Available somatic recurrence evidence was not sufficient for a germline PS4 call
Sources
oncokb ↗clinvar ↗
PM1 A hotspot signal was suggested, but the reviewed hotspot evidence for codon 626 was marked uncertain and did not confirm that this exact residue is an established mutational hotspot or critical benign-variant-depleted region. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review was marked uncertain and needs human review
  • OncoKB supports somatic relevance of the variant but does not by itself establish PM1
Still missing
  • Exact codon 626 hotspot confirmation was not established
  • Residue-level recurrence requires direct confirmation
Sources
hotspots ↗oncokb ↗
PM3 No evidence was identified showing this variant in trans with a pathogenic variant for a recessive disorder. Details ▾Hide ▴
Still missing
  • No phase data were identified
  • No recessive case data were identified
PM5 No evidence was identified showing a different pathogenic missense change at the same codon that would support PM5. Details ▾Hide ▴
Still missing
  • No same-codon pathogenic comparison was established
PM6 No presumed de novo occurrence without confirmed parentage was identified. Details ▾Hide ▴
Evidence considered
  • ClinVar search was negative for this variant
Still missing
  • No inheritance report was identified for this variant
Sources
clinvar ↗
PP1 No segregation data were identified to show co-segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission with segregation information was available
Still missing
  • No pedigree or family segregation data were identified
Sources
clinvar ↗
PP2 Available evidence shows SF3B1 missense variation can be clinically relevant, but no gene-specific missense-rate framework was identified to support applying PP2 in this case. Details ▾Hide ▴
Evidence considered
  • Variant-specific somatic missense curation exists in OncoKB
Still missing
  • No gene-specific PP2 rule or missense constraint framework was identified
Sources
oncokb ↗
PP4 No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for an SF3B1-related disorder. Details ▾Hide ▴
Still missing
  • Clinical phenotype data were not available for review
PP5 No qualifying pathogenic classification from a germline clinical database or other accepted external clinical source was identified for this variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • ClinVar contained no submission for this variant
Sources
clinvar ↗
BS2 The variant is very rare in population databases and no evidence was identified showing observation in healthy adults at a frequency sufficient to support BS2. Details ▾Hide ▴
Evidence considered
  • No homozygotes reported in gnomAD v2.1
  • No homozygotes reported in gnomAD v4.1
Still missing
  • No healthy adult cohort evidence beyond gnomAD rarity was identified
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No published functional study specific to p.(Asn626Asp) was identified showing normal protein function or a benign effect. Details ▾Hide ▴
Evidence considered
  • No PMID-backed benign functional result was captured for this exact variant
Still missing
  • No exact-variant benign functional assay result was retrieved
Sources
oncokb ↗
BS4 No family data were identified showing lack of segregation between this variant and disease. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission with family non-segregation information was available
Still missing
  • No informative non-segregation data were identified
Sources
clinvar ↗
BP2 No case-level phase information was identified to determine whether this variant occurs in trans with a pathogenic variant or in cis with another variant. Details ▾Hide ▴
Still missing
  • No phase data were identified
BP3 No evidence was identified showing that this missense change is located in a repetitive region without known function. Details ▾Hide ▴
Still missing
  • No domain or repeat annotation supporting BP3 was identified
BP5 No alternate molecular diagnosis or variant explanation was provided that would account for the phenotype independently of this variant. Details ▾Hide ▴
Still missing
  • No case-level differential genetic diagnosis information was available
BP6 No qualifying benign classification from a germline clinical database or other accepted external clinical source was identified for this variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • ClinVar contained no submission for this variant
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, or canonical +/-1,2 splice variant, so the generic PVS1 loss-of-function framework does not apply. Details ▾Hide ▴
Evidence considered
  • SF3B1 was considered eligible for generic PVS1 review at the gene level
  • c.1876A>G was placed outside the generic null-variant buckets
  • Splice consensus involvement was not identified
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis variant is a missense substitution and does not create a protein length change or in-frame exon-level alteration. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Asn626Asp)
BP1 N/AThis is a missense variant in a gene with established clinically relevant missense variation, so BP1 does not fit this variant-gene context. Details ▾Hide ▴
Evidence considered
  • OncoKB contains a variant-specific missense entry for SF3B1
Sources
oncokb ↗
BP7 N/ABP7 is for synonymous or certain intronic variants, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Asn626Asp)

Identifiers

Gene
SF3B1
Transcript
NM_012433.2
Coding (HGVS c.)
NM_012433.2:c.1876A>G
Protein (HGVS p.)
NP_036565.2:p.(Asn626Asp)
GRCh38
chr2:197402757 T>C
GRCh37
chr2:198267481 T>C

Gene diagram

Every interpreted variant in SF3B1, mapped onto the exon structure of NM_012433.2. Select a row to find it on the plot.

SF3B1NM_012433.2
Fetching transcript structure from UCSC…
gnomAD v4.1 8 / 1,613,994 alleles AF 4.96e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1 1 / 251,158 alleles AF 3.98e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 5e-06 · 8 / 1,613,994 alleles · 0 hom · FAF 1.2e-06
Remaining individuals2 / 62,482 3.2e-05
Admixed American1 / 60,000 1.7e-05
European (non-Finnish)5 / 1,179,978 4.2e-06
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 251,158 alleles · 0 hom
Admixed American1 / 34,556 2.9e-05
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.95665e-06; MAF= 0.00050%, 8/1613994 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20092e-05; MAF= 0.00320%, 2/62482 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98156e-06; MAF= 0.00040%, 1/251158 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89385e-05; MAF= 0.00289%, 1/34556 alleles, homozygotes = 0).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Computational evidence is mixed. REVEL is 0.60, BayesDel is -0.0733292, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, so in silico results do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.60
  • BayesDel -0.0733292
  • SpliceAI max delta 0.08
Still missing
  • No concordant computational signal was present across available predictors
Sources
revelbayesdelspliceai ↗
BP4 Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact (max delta 0.08), but REVEL is 0.60 and BayesDel is -0.0733292, so the overall in silico profile is mixed. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.08
  • REVEL 0.60
  • BayesDel -0.0733292
Still missing
  • No concordant benign computational signal was present across available predictors
Sources
spliceai ↗revelbayesdel
BP7 N/ABP7 is for synonymous or certain intronic variants, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Asn626Asp)

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.6. BayesDel score = -0.0733292.

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 8 / 1,613,994 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record 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= 4.95665e-06; MAF= 0.00050%, 8/1613994 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20092e-05; MAF= 0.00320%, 2/62482 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98156e-06; MAF= 0.00040%, 1/251158 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89385e-05; MAF= 0.00289%, 1/34556 alleles, homozygotes = 0).

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.6. BayesDel score = -0.0733292.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59206442, n = 12 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.