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SF3B1c.1986C>AUncertain significance
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Variant interpretation report

SF3B1 c.1986C>A, p.(His662Gln)

NM_012433.4:c.1986C>A NP_036565.2:p.(His662Gln) 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

This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (7/1613874 alleles; AF 4.33739e-06; highest population AF 3.12354e-05 in Finnish individuals; grpmax FAF 6.8e-07), which is below the 0.1% rarity threshold and supports PM2.

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
7 / 1,613,874 alleles

gnomAD v4.1: 7 / 1,613,874 alleles. Recorded AF 4.33739e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251370 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
SpliceAI score
0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. 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 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
26 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV59205547, n = 26 times).

Cancer Hotspots

This variant does not lie 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 · 6 not met · 13 not assessed · 8 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.1986C>A (p.His662Gln) variant has been observed in somatic cancer curation resources and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (7/1613874 alleles; AF 4.33739e-06; highest population AF 3.12354e-05), which is below the 0.1% rarity threshold used for PM2.

Published studies showed that SF3B1 pathway mutations and SF3B1 disruption can alter RNA splicing, growth, and erythroid differentiation, but a well-established assay specific to p.His662Gln was not identified.

In silico results were mixed, with REVEL 0.628 and BayesDel 0.0218, while SpliceAI predicted no significant splice impact with a maximum delta score of 0.07, so computational evidence did not support PP3 or BP4.

Met · 1

PM2 SupportingThis variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (7/1613874 alleles; AF 4.33739e-06; highest population AF 3.12354e-05 in Finnish individuals; grpmax FAF 6.8e-07), which is below the 0.1% rarity threshold and supports PM2. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0/251370 alleles
  • gnomAD v4.1: 7/1613874 alleles
  • AF 4.33739e-06
  • grpmax FAF 6.8e-07
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 6 · evaluated, threshold not reached

PS4 This variant has been observed in somatic cancer resources and is absent from ClinVar, but no germline case-control study or affected-individual enrichment dataset for this exact variant was identified, so PS4 is not met. Details ▾Hide ▴
Evidence considered
  • Variant-specific oncologic curation was present in OncoKB
  • ClinVar search returned no germline submission for this variant
Still missing
  • No exact-variant germline prevalence or odds-ratio data were identified.
Sources
oncokb ↗clinvar ↗
PM1 Available hotspot review did not confirm that p.(His662Gln) lies in a statistically significant hotspot or a well-established critical region without benign variation, so PM1 is not met. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review reported no hotspot row found for SF3B1 H662 and marked the result uncertain
Still missing
  • Residue-level hotspot confirmation remained uncertain and was flagged for human review.
Sources
hotspots ↗
PP3 Computational evidence is not sufficiently concordant to support PP3. REVEL was 0.628 and BayesDel was 0.0218, while SpliceAI predicted no significant splice effect with a maximum delta score of 0.07. Details ▾Hide ▴
Evidence considered
  • REVEL 0.628
  • BayesDel 0.0218
  • SpliceAI max delta 0.07
Still missing
  • No stronger or more concordant deleterious computational evidence was identified.
Sources
revelbayesdelspliceai ↗
BA1 Population frequency does not meet the benign stand-alone threshold. The highest observed population frequency in gnomAD v4.1 was 3.12354e-05, which is far below the 1% threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 highest population AF 3.12354e-05
Sources
gnomad_v4 ↗
BS1 Population frequency does not meet the benign strong threshold. The highest observed population frequency in gnomAD v4.1 was 3.12354e-05, which is below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 highest population AF 3.12354e-05
Sources
gnomad_v4 ↗
BP4 Computational evidence does not support a benign interpretation. REVEL was 0.628 and BayesDel was 0.0218, and SpliceAI predicted no significant splice effect with a maximum delta score of 0.07; these results are not sufficient to support BP4. Details ▾Hide ▴
Evidence considered
  • REVEL 0.628
  • BayesDel 0.0218
  • SpliceAI max delta 0.07
Still missing
  • No concordant benign computational profile was identified.
Sources
revelbayesdelspliceai ↗

Not assessed · 13 · no assessment recorded

PS1 No pathogenic or likely pathogenic comparator producing the same amino acid change was identified in the available sources, so PS1 could not be established. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result for this variant
Still missing
  • A same-amino-acid pathogenic comparator was not identified.
Sources
clinvar ↗
PS2 No confirmed de novo occurrence with established maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo evidence was identified in the reviewed materials
Still missing
  • No parentage-confirmed de novo case report was identified.
PS3 Published studies showed that SF3B1 pathway mutations and SF3B1 disruption can alter RNA splicing and hematopoietic function, but no well-established functional assay specific to p.(His662Gln) demonstrating a damaging effect was identified. Details ▾Hide ▴
Evidence considered
  • PMID:21909114 described recurrent SF3B1 pathway mutations with abnormal RNA splicing in myelodysplasia
  • PMID:25428262 reported that SF3B1 knockdown and SF3B1-mutant MDS cells showed altered splicing and gene expression
  • OncoKB linked this variant to curated functional literature
Still missing
  • No variant-specific well-established functional assay for p.(His662Gln) was identified.
Sources
PMID:21909114 ↗PMID:25428262 ↗oncokb ↗
PM6 No assumed de novo occurrence without parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No PM6-level evidence was identified in the reviewed materials
Still missing
  • No de novo case report without full parentage confirmation was identified.
PP1 No segregation data were identified for this variant in affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation evidence was identified
Still missing
  • No pedigree or cosegregation data were identified.
PP2 Available evidence did not establish a gene-specific missense-constraint rule suitable to apply PP2 for this variant. Details ▾Hide ▴
Still missing
  • No SF3B1-specific PP2 framework was identified.
PP4 No phenotype-specific clinical information was provided to determine whether the presentation is highly specific for an SF3B1-related disorder. Details ▾Hide ▴
Still missing
  • Phenotypic details and diagnostic context were not available.
BS2 Available population data do not establish observation of this variant in healthy individuals in a manner sufficient to apply BS2. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 reported 0 homozygotes
Still missing
  • No BS2-qualifying healthy adult observation dataset was identified.
Sources
gnomad_v4 ↗
BS3 Published studies showed functional consequences of SF3B1 disruption and broader SF3B1 pathway mutations, but no well-established assay specific to p.(His662Gln) demonstrating normal function was identified. Details ▾Hide ▴
Evidence considered
  • PMID:21909114 reported abnormal splicing associated with SF3B1 pathway mutations
  • PMID:25428262 reported altered growth
  • differentiation
  • and splicing after SF3B1 disruption
  • OncoKB linked this variant to curated functional literature
Still missing
  • No variant-specific normal-function assay was identified.
Sources
PMID:21909114 ↗PMID:25428262 ↗oncokb ↗
BS4 No informative family data were identified showing lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No BS4-level pedigree evidence was identified
Still missing
  • No non-segregation evidence was identified.
BP2 No phase data or alternate molecular diagnosis information were identified to support BP2. Details ▾Hide ▴
Still missing
  • No cis/trans configuration data were identified.
BP3 No evidence was identified that this missense change lies in a repetitive region without known function. Details ▾Hide ▴
Still missing
  • No repeat-region assessment was available.
BP5 No alternate molecular cause was provided that would explain the phenotype independently of this variant. Details ▾Hide ▴
Still missing
  • Clinical and broader molecular diagnostic context were not available.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AGene-level review supports considering generic PVS1 for true loss-of-function variants in SF3B1, but NM_012433.4:c.1986C>A is a missense substitution and does not fall within the nonsense, frameshift, or canonical +/-1,2 splice categories used by the generic PVS1 framework. Details ▾Hide ▴
Evidence considered
  • pvs1_gene_context marked SF3B1 PVS1 gate as eligible for true loss-of-function variants
  • pvs1_variant_assessment stated this variant is not in a default generic PVS1 null-variant bucket
Still missing
  • No SF3B1-specific PVS1 framework was available beyond generic fallback.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ANo evidence was identified for this variant in trans with a pathogenic variant in a recessive disease context, so PM3 does not apply. Details ▾Hide ▴
Still missing
  • No recessive/trans configuration data were identified.
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 does not apply. Details ▾Hide ▴
Evidence considered
  • Variant consequence is missense p.(His662Gln)
PM5 N/AClassic same-residue PM5 semantics could not be confirmed safely for this gene/framework, and no validated same-residue pathogenic or likely pathogenic comparator was established for use here. Details ▾Hide ▴
Evidence considered
  • pm5_candidates marked classic PM5 search as not eligible and did not identify comparator variants
Still missing
  • No governing same-residue PM5 rule was confirmed for this case.
Sources
pm5_candidates
PP5 N/ANo reputable external pathogenic classification for this variant was identified in the reviewed germline sources. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result
Still missing
  • No germline pathogenic assertion from a qualifying source was identified.
Sources
clinvar ↗
BP1 N/ABP1 does not apply because the available evidence does not indicate a disease mechanism in which truncating variants predominate and missense variation is generally expected to be benign for SF3B1. Details ▾Hide ▴
Evidence considered
  • SF3B1 germline literature includes both predicted loss-of-function and missense constitutional variants
Sources
pvs1_gene_context
BP6 N/ANo reputable external benign classification for this variant was identified in the reviewed germline sources. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result
Still missing
  • No qualifying benign assertion was identified.
Sources
clinvar ↗
BP7 N/ABP7 does not apply because this variant is missense rather than synonymous or intronic outside the splice region. Details ▾Hide ▴
Evidence considered
  • Variant consequence is missense p.(His662Gln)

Identifiers

Gene
SF3B1
Transcript
NM_012433.4
Coding (HGVS c.)
NM_012433.4:c.1986C>A
Protein (HGVS p.)
NP_036565.2:p.(His662Gln)
GRCh38
chr2:197402647 G>T
GRCh37
chr2:198267371 G>T
COSMIC
COSV59205547

Gene diagram

Every interpreted variant in SF3B1, mapped onto the exon structure of NM_012433.4. Select a row to find it on the plot.

SF3B1NM_012433.4
Fetching transcript structure from UCSC…
gnomAD v4.1 7 / 1,613,874 alleles AF 4.34e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 0 / 251,370 alleles AF 0 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 4.3e-06 · 7 / 1,613,874 alleles · 0 hom · FAF 6.8e-07
European (Finnish)2 / 64,030 3.1e-05
African/African American1 / 74,916 1.3e-05
South Asian1 / 91,086 1.1e-05
European (non-Finnish)3 / 1,179,872 2.5e-06
0 alternate alleles recorded in 6 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish.

gnomAD v2.1

AF 0 · 0 / 251,370 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.33739e-06; MAF= 0.00043%, 7/1613874 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12354e-05; MAF= 0.00312%, 2/64030 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251370 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).

SpliceAI and Pangolin

SpliceAI acceptor lossat -492 bp
0.000
SpliceAI acceptor gainat -134 bp
0.010
SpliceAI donor lossat -91 bp
0.000
SpliceAI donor gainat -4 bp
0.070
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.070

Other predictors

REVEL
0.628
BayesDel
0.022

How the predictions were used

PP3 Computational evidence is not sufficiently concordant to support PP3. REVEL was 0.628 and BayesDel was 0.0218, while SpliceAI predicted no significant splice effect with a maximum delta score of 0.07. Details ▾Hide ▴
Evidence considered
  • REVEL 0.628
  • BayesDel 0.0218
  • SpliceAI max delta 0.07
Still missing
  • No stronger or more concordant deleterious computational evidence was identified.
Sources
revelbayesdelspliceai ↗
BP4 Computational evidence does not support a benign interpretation. REVEL was 0.628 and BayesDel was 0.0218, and SpliceAI predicted no significant splice effect with a maximum delta score of 0.07; these results are not sufficient to support BP4. Details ▾Hide ▴
Evidence considered
  • REVEL 0.628
  • BayesDel 0.0218
  • SpliceAI max delta 0.07
Still missing
  • No concordant benign computational profile was identified.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 does not apply because this variant is missense rather than synonymous or intronic outside the splice region. Details ▾Hide ▴
Evidence considered
  • Variant consequence is missense p.(His662Gln)

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.628. BayesDel score = 0.0218.

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Frequent pathway mutations of splicing machinery in myelodysplasia.
    No paper-specific finding is recorded.
    PMID 21909114 ↗
  • Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.
    No paper-specific finding is recorded.
    PMID 25428262 ↗

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

gnomAD v4.1 7 / 1,613,874 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.070 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= 4.33739e-06; MAF= 0.00043%, 7/1613874 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12354e-05; MAF= 0.00312%, 2/64030 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251370 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.628. BayesDel score = 0.0218.

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59205547, n = 26 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.