11-64770347-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004630.4(SF1):​c.298C>T​(p.Arg100Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SF1
NM_004630.4 missense

Scores

15
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.30
Variant links:
Genes affected
SF1 (HGNC:12950): (splicing factor 1) This gene encodes a nuclear pre-mRNA splicing factor. The encoded protein specifically recognizes the intron branch point sequence at the 3' splice site, together with the large subunit of U2 auxiliary factor (U2AF), and is required for the early stages of spliceosome assembly. It also plays a role in nuclear pre-mRNA retention and transcriptional repression. The encoded protein contains an N-terminal U2AF ligand motif, a central hnRNP K homology motif and quaking 2 region which bind a key branch-site adenosine within the branch point sequence, a zinc knuckles domain, and a C-terminal proline-rich domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SF1NM_004630.4 linkuse as main transcriptc.298C>T p.Arg100Cys missense_variant 4/13 ENST00000377390.8 NP_004621.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SF1ENST00000377390.8 linkuse as main transcriptc.298C>T p.Arg100Cys missense_variant 4/131 NM_004630.4 ENSP00000366607 A1Q15637-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461796
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
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 GeneticsJan 24, 2024The c.673C>T (p.R225C) alteration is located in exon 4 (coding exon 4) of the SF1 gene. This alteration results from a C to T substitution at nucleotide position 673, causing the arginine (R) at amino acid position 225 to be replaced by a cysteine (C). 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
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
.;D;.;.;.;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D;D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Pathogenic
3.6
.;H;H;H;H;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.9
D;D;D;D;D;D
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
D;.;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;.
Vest4
0.73
MutPred
0.50
.;Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);.;
MVP
0.95
MPC
3.6
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.99

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: rs1281550052; hg19: chr11-64537819; API