2-197401887-C-G

Position:

• chr2-197401887-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_012433.4(SF3B1):​c.2225G>C​(p.Gly742Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G742D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SF3B1 NM_012433.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002199
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.85

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-197401887-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376530.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.2225G>C	p.Gly742Ala	missense_variant, splice_region_variant	16/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.1787G>C	p.Gly596Ala	missense_variant, splice_region_variant	13/22
SF3B1	XM_047443839.1	c.1787G>C	p.Gly596Ala	missense_variant, splice_region_variant	13/22
SF3B1	XM_047443840.1	c.2225G>C	p.Gly742Ala	missense_variant, splice_region_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.2225G>C	p.Gly742Ala	missense_variant, splice_region_variant	16/25	1	NM_012433.4	P1
SF3B1	ENST00000470268.2	n.4109G>C		splice_region_variant, non_coding_transcript_exon_variant	15/24	2
SF3B1	ENST00000652026.1	c.*3292G>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	16/25
SF3B1	ENST00000652738.1	c.*2484G>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	17/26

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.034
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.35
Sift	Benign	0.29	T
Sift4G	Benign	0.58	T
Polyphen		0.20	B
Vest4		0.70
MutPred		0.50		Loss of catalytic residue at G742 (P = 0.0478);
MVP		0.69
MPC		1.8
ClinPred		0.79	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-198266611;