chr2-197402108-T-G

Position:

• chr2-197402108-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PM5 PP5

The NM_012433.4(SF3B1):​c.2100A>C​(p.Lys700Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin 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: 32)
• Consequence: SF3B1 NM_012433.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.02

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

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_012433.4 (SF3B1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376040
• PM1: In a repeat HEAT 5 (size 38) in uniprot entity SF3B1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_012433.4
• 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 id is 376004.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 2-197402108-T-G is Pathogenic according to our data. Variant chr2-197402108-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376041.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.2100A>C	p.Lys700Asn	missense_variant	15/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.1662A>C	p.Lys554Asn	missense_variant	12/22
SF3B1	XM_047443839.1	c.1662A>C	p.Lys554Asn	missense_variant	12/22
SF3B1	XM_047443840.1	c.2100A>C	p.Lys700Asn	missense_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.2100A>C	p.Lys700Asn	missense_variant	15/25	1	NM_012433.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.54		Loss of ubiquitination at K700 (P = 0.0183);
MVP		0.75
MPC		3.1
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.8
Varity_R		0.88
gMVP		0.87

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

Other links and lift over

dbSNP: rs1057519755; hg19: chr2-198266832;