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GeneBe

17-58007008-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_006924.5(SRSF1):c.130G>A(p.Asp44Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

SRSF1
NM_006924.5 missense

Scores

2
5
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.06
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain RRM 1 (size 75) in uniprot entity SRSF1_HUMAN there are 8 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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRSF1NM_006924.5 linkuse as main transcriptc.130G>A p.Asp44Asn missense_variant 1/4 ENST00000258962.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRSF1ENST00000258962.5 linkuse as main transcriptc.130G>A p.Asp44Asn missense_variant 1/41 NM_006924.5 P1Q07955-1
ENST00000624641.2 linkuse as main transcriptn.357C>T non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability;C4022738:Neurodevelopmental delay Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneFeb 15, 2023- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 16, 2023De novo variant with confirmed parentage in a patient with neurodevelopmental features in the published literature (PMID: 37071997); Published functional studies indicate that this variant allows SRSF1 to retain splicing activity and may not lead to a loss of function (Bogaert et al., 2023); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37071997) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Pathogenic
26
DANN
Uncertain
0.99
Eigen
Benign
0.10
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.92
D
M_CAP
Benign
0.0059
T
MetaRNN
Uncertain
0.56
D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M;.;.;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.89
D
Sift4G
Benign
0.34
T;T;T;T
Polyphen
0.029
.;.;.;B
Vest4
0.73
MutPred
0.29
Gain of MoRF binding (P = 0.0653);Gain of MoRF binding (P = 0.0653);Gain of MoRF binding (P = 0.0653);Gain of MoRF binding (P = 0.0653);
MVP
0.37
MPC
1.8
ClinPred
0.96
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.83

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: chr17-56084369; API