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GeneBe

17-58005420-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_006924.5(SRSF1):c.733C>T(p.Arg245Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,754 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: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SRSF1
NM_006924.5 missense

Scores

5
4
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.38
Variant links:
Genes affected
SRSF1 (HGNC:10780): (serine and arginine rich splicing factor 1) This gene encodes a member of the arginine/serine-rich splicing factor protein family. The encoded protein can either activate or repress splicing, depending on its phosphorylation state and its interaction partners. Multiple transcript variants have been found for this gene. There is a pseudogene of this gene on chromosome 13. [provided by RefSeq, Jun 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a chain Serine/arginine-rich splicing factor 1 (size 246) in uniprot entity SRSF1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_006924.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, SRSF1
BP4
Computational evidence support a benign effect (MetaRNN=0.36600965).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRSF1NM_006924.5 linkuse as main transcriptc.733C>T p.Arg245Cys missense_variant 4/4 ENST00000258962.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRSF1ENST00000258962.5 linkuse as main transcriptc.733C>T p.Arg245Cys missense_variant 4/41 NM_006924.5 P1Q07955-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461754
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727150
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

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 28, 2023The c.733C>T (p.R245C) alteration is located in exon 4 (coding exon 4) of the SRSF1 gene. This alteration results from a C to T substitution at nucleotide position 733, causing the arginine (R) at amino acid position 245 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
Uncertain
0.41
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
34
DANN
Benign
0.95
DEOGEN2
Benign
0.081
T;T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.37
T;T
MetaSVM
Benign
-0.77
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.88
D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.51
MutPred
0.42
Loss of methylation at R245 (P = 0.0163);Loss of methylation at R245 (P = 0.0163);
MVP
0.53
MPC
2.2
ClinPred
0.79
D
GERP RS
5.7
Varity_R
0.18
gMVP
0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-56082781; API