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GeneBe

16-70556991-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_012426.5(SF3B3):c.1972G>A(p.Gly658Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SF3B3
NM_012426.5 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
SF3B3 (HGNC:10770): (splicing factor 3b subunit 3) This gene encodes subunit 3 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. Subunit 3 has also been identified as a component of the STAGA (SPT3-TAF(II)31-GCN5L acetylase) transcription coactivator-HAT (histone acetyltransferase) complex, and the TFTC (TATA-binding-protein-free TAF(II)-containing complex). These complexes may function in chromatin modification, transcription, splicing, and DNA repair. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, SF3B3
BP4
Computational evidence support a benign effect (MetaRNN=0.40886992).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SF3B3NM_012426.5 linkuse as main transcriptc.1972G>A p.Gly658Ser missense_variant 15/26 ENST00000302516.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SF3B3ENST00000302516.10 linkuse as main transcriptc.1972G>A p.Gly658Ser missense_variant 15/261 NM_012426.5 P1Q15393-1
SF3B3ENST00000567250.5 linkuse as main transcriptn.1046G>A non_coding_transcript_exon_variant 5/53

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152072
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250236
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135242
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461378
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727004
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152072
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 07, 2023The c.1972G>A (p.G658S) alteration is located in exon 15 (coding exon 14) of the SF3B3 gene. This alteration results from a G to A substitution at nucleotide position 1972, causing the glycine (G) at amino acid position 658 to be replaced by a serine (S). 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
Benign
0.076
BayesDel_addAF
Benign
-0.076
T
BayesDel_noAF
Benign
-0.18
Cadd
Uncertain
23
Dann
Uncertain
0.98
DEOGEN2
Benign
0.041
T
Eigen
Benign
-0.0083
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.0059
T
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.14
N
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
0.44
N
REVEL
Benign
0.28
Sift
Benign
0.47
T
Sift4G
Benign
0.64
T
Polyphen
0.0
B
Vest4
0.82
MutPred
0.36
Gain of phosphorylation at G658 (P = 0.0532);
MVP
0.78
MPC
1.0
ClinPred
0.41
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.17
gMVP
0.37

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.

Other links and lift over

dbSNP: rs1303778752; hg19: chr16-70590894; API