2-197402110-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP2PP5BS2

The NM_012433.4(SF3B1):c.2098A>G(p.Lys700Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000449 in 1,604,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K700I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

SF3B1
NM_012433.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

SF3B1 (HGNC:10768): (splicing factor 3b subunit 1) This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 have 22 non-identical, tandem HEAT repeats that form rod-like, helical structures. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

SF3B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a mutagenesis_site Does not affect the stability of the SF3B complex interaction with U2AF65. Does not decrease the affinity to RNA. (size 0) in uniprot entity SF3B1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_012433.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-197402109-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376042.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant where missense usually causes diseases, SF3B1

PP5

Variant 2-197402110-T-C is Pathogenic according to our data. Variant chr2-197402110-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376004.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

BS2

High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SF3B1	NM_012433.4 linkuse as main transcript	c.2098A>G	p.Lys700Glu	missense_variant	15/25	ENST00000335508.11
SF3B1	XM_047443838.1 linkuse as main transcript	c.1660A>G	p.Lys554Glu	missense_variant	12/22
SF3B1	XM_047443839.1 linkuse as main transcript	c.1660A>G	p.Lys554Glu	missense_variant	12/22
SF3B1	XM_047443840.1 linkuse as main transcript	c.2098A>G	p.Lys700Glu	missense_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11 linkuse as main transcript	c.2098A>G	p.Lys700Glu	missense_variant	15/25	1	NM_012433.4	P1	O75533-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000897

AC:

AN:

245240

Hom.:

AF XY:

0.0000979

AC XY:

AN XY:

132820

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.0000311

Gnomad ASJ exome

AF:

0.000306

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000676

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000455

AC:

AN:

1451952

Hom.:

Cov.:

AF XY:

0.0000596

AC XY:

AN XY:

721254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000234

Gnomad4 ASJ exome

AF:

0.000193

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000488

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000484

Hom.:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chronic myelogenous leukemia, BCR-ABL1 positive

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Druker Lab, Oregon Health and Sciences University

Oct 10, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2021

- -

Acute myeloid leukemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

SF3B1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2022

The SF3B1 c.2098A>G variant is predicted to result in the amino acid substitution p.Lys700Glu. To our knowledge, this variant has not been reported in the literature in association with human disease. This variant is reported in 0.030% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-198266834-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.62

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.69

MVP

0.76

MPC

3.4

ClinPred

0.91

GERP RS

6.0

Varity_R

0.92

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over