rs1057519756

Variant names:

• chr2-197402109-T-A
• rs1057519756
• NM_012433.4:c.2099A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-197402109-T-A
• chr2-197402109-T-C
• chr2-197402109-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_012433.4(SF3B1):​c.2099A>T​(p.Lys700Ile) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K700E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SF3B1 NM_012433.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 5 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-197402110-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376004.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3B1	NM_012433.4	MANE Select	c.2099A>T	p.Lys700Ile	missense	Exon 15 of 25	NP_036565.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3B1	ENST00000335508.11	TSL:1 MANE Select	c.2099A>T	p.Lys700Ile	missense	Exon 15 of 25	ENSP00000335321.6
	SF3B1	ENST00000462613.1	TSL:3	n.54A>T		non_coding_transcript_exon	Exon 2 of 2
	SF3B1	ENST00000470268.2	TSL:2	n.3983A>T		non_coding_transcript_exon	Exon 14 of 24

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.56		Loss of disorder (P = 0.0178)
MVP		0.67
MPC		4.3
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.8
Varity_R		0.94
gMVP		0.89
Mutation Taster		=24/76	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519756; hg19: chr2-198266833;