1-37978722-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006802.4(SF3A3):​c.933G>C​(p.Lys311Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,555,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

SF3A3
NM_006802.4 missense, splice_region

Scores

1
4
14
Splicing: ADA: 0.0002724
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.300
Variant links:
Genes affected
SF3A3 (HGNC:10767): (splicing factor 3a subunit 3) This gene encodes subunit 3 of the splicing factor 3a protein complex. The splicing factor 3a heterotrimer includes subunits 1, 2 and 3 and is necessary for the in vitro conversion of 15S U2 snRNP into an active 17S particle that performs pre-mRNA splicing. Subunit 3 interacts with subunit 1 through its amino-terminus while the zinc finger domain of subunit 3 plays a role in its binding to the 15S U2 snRNP. This gene has a pseudogene on chromosome 20. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07636958).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SF3A3NM_006802.4 linkc.933G>C p.Lys311Asn missense_variant, splice_region_variant Exon 11 of 17 ENST00000373019.5 NP_006793.1 Q12874
SF3A3NM_001320830.2 linkc.774G>C p.Lys258Asn missense_variant, splice_region_variant Exon 9 of 15 NP_001307759.1 B4DW90

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SF3A3ENST00000373019.5 linkc.933G>C p.Lys311Asn missense_variant, splice_region_variant Exon 11 of 17 1 NM_006802.4 ENSP00000362110.4 Q12874
SF3A3ENST00000460925.1 linkn.478G>C splice_region_variant, non_coding_transcript_exon_variant Exon 1 of 4 2
SF3A3ENST00000489537.5 linkn.*1G>C downstream_gene_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000421
AC:
7
AN:
166168
Hom.:
0
AF XY:
0.0000343
AC XY:
3
AN XY:
87578
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000237
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000812
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:
0.00000570
AC:
8
AN:
1403266
Hom.:
0
Cov.:
31
AF XY:
0.00000433
AC XY:
3
AN XY:
692900
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000193
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000274
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:
0.0000131
AC:
2
AN:
152308
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
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:
0.0000151
ExAC
AF:
0.0000171
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 06, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.933G>C (p.K311N) alteration is located in exon 11 (coding exon 11) of the SF3A3 gene. This alteration results from a G to C substitution at nucleotide position 933, causing the lysine (K) at amino acid position 311 to be replaced by an asparagine (N). 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
Uncertain
0.55
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.022
T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.0076
T
MetaRNN
Benign
0.076
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
PrimateAI
Pathogenic
0.79
T
PROVEAN
Benign
-0.30
N
REVEL
Benign
0.046
Sift
Benign
0.50
T
Sift4G
Benign
0.38
T
Polyphen
0.45
B
Vest4
0.34
MutPred
0.32
Loss of methylation at K311 (P = 0.0127);
MVP
0.44
MPC
1.2
ClinPred
0.046
T
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.15
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00027
dbscSNV1_RF
Benign
0.0020
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: rs182702407; hg19: chr1-38444394; API