NM_012433.4:c.2264C>T

Variant names:

• chr2-197401848-G-A
• rs2105984507
• NM_012433.4:c.2264C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012433.4(SF3B1):​c.2264C>T​(p.Pro755Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SF3B1 NM_012433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B1	NM_012433.4	c.2264C>T	p.Pro755Leu	missense_variant	Exon 16 of 25	ENST00000335508.11	NP_036565.2
SF3B1	XM_047443838.1	c.1826C>T	p.Pro609Leu	missense_variant	Exon 13 of 22		XP_047299794.1
SF3B1	XM_047443839.1	c.1826C>T	p.Pro609Leu	missense_variant	Exon 13 of 22		XP_047299795.1
SF3B1	XM_047443840.1	c.2264C>T	p.Pro755Leu	missense_variant	Exon 16 of 22		XP_047299796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B1	ENST00000335508.11	c.2264C>T	p.Pro755Leu	missense_variant	Exon 16 of 25	1	NM_012433.4	ENSP00000335321.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2264C>T (p.P755L) alteration is located in exon 16 (coding exon 16) of the SF3B1 gene. This alteration results from a C to T substitution at nucleotide position 2264, causing the proline (P) at amino acid position 755 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.54		Gain of catalytic residue at P755 (P = 0.0457);
MVP		0.86
MPC		2.8
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.91
gMVP		0.92
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2105984507; hg19: chr2-198266572;