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17-76736877-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM5PP2PP5_ModerateBS2_Supporting

The NM_001195427.2(SRSF2):c.284C>G(p.Pro95Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000391 in 1,610,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P95L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

SRSF2
NM_001195427.2 missense

Scores

4
8
6

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.00
Variant links:
Genes affected
SRSF2 (HGNC:10783): (serine and arginine rich splicing factor 2) The protein encoded by this gene is a member of the serine/arginine (SR)-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. Each of these factors contains an RNA recognition motif (RRM) for binding RNA and an RS domain for binding other proteins. The RS domain is rich in serine and arginine residues and facilitates interaction between different SR splicing factors. In addition to being critical for mRNA splicing, the SR proteins have also been shown to be involved in mRNA export from the nucleus and in translation. Two transcript variants encoding the same protein and one non-coding transcript variant have been found for this gene. In addition, a pseudogene of this gene has been found on chromosome 11. [provided by RefSeq, Sep 2010]
MFSD11 (HGNC:25458): (major facilitator superfamily domain containing 11) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-76736877-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2504111.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant where missense usually causes diseases, SRSF2
PP5
Variant 17-76736877-G-C is Pathogenic according to our data. Variant chr17-76736877-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 998075.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRSF2NM_001195427.2 linkuse as main transcriptc.284C>G p.Pro95Arg missense_variant 1/3 ENST00000359995.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRSF2ENST00000359995.10 linkuse as main transcriptc.284C>G p.Pro95Arg missense_variant 1/31 NM_001195427.2 P1Q01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152068
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000292
AC:
7
AN:
239480
Hom.:
0
AF XY:
0.0000455
AC XY:
6
AN XY:
131866
show subpopulations
Gnomad AFR exome
AF:
0.000141
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000470
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000350
AC:
51
AN:
1458860
Hom.:
0
Cov.:
31
AF XY:
0.0000551
AC XY:
40
AN XY:
725596
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000580
Gnomad4 NFE exome
AF:
0.0000378
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152068
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000478
ExAC
AF:
0.0000749
AC:
9

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Acute megakaryoblastic leukemia in down syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaSep 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.17
CADD
Pathogenic
26
DANN
Benign
0.87
DEOGEN2
Uncertain
0.42
T;T;.;.;T
Eigen
Uncertain
0.32
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.91
D
M_CAP
Pathogenic
0.98
D
MetaRNN
Uncertain
0.68
D;D;D;D;D
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Uncertain
2.6
M;M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.0
D;.;.;.;N
REVEL
Uncertain
0.41
Sift
Uncertain
0.021
D;.;.;.;D
Sift4G
Benign
0.20
T;T;T;T;.
Polyphen
1.0
D;D;.;.;.
Vest4
0.45
MVP
0.58
MPC
2.8
ClinPred
0.65
D
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.58
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs751713049; hg19: chr17-74732959; COSMIC: COSV57969809; COSMIC: COSV57969809; API