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GeneBe

1-29150188-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_005626.5(SRSF4):c.583C>T(p.Arg195Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

SRSF4
NM_005626.5 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.65
Variant links:
Genes affected
SRSF4 (HGNC:10786): (serine and arginine rich splicing factor 4) Enables RNA binding activity. Involved in negative regulation of mRNA splicing, via spliceosome. Located in nuclear speck. Biomarker of Down syndrome; acute myeloid leukemia; clear cell renal cell carcinoma; and colon adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2
Missense variant where missense usually causes diseases, SRSF4
BS2
High AC in GnomAdExome4 at 69 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRSF4NM_005626.5 linkuse as main transcriptc.583C>T p.Arg195Cys missense_variant 5/6 ENST00000373795.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRSF4ENST00000373795.7 linkuse as main transcriptc.583C>T p.Arg195Cys missense_variant 5/61 NM_005626.5 P1
SRSF4ENST00000466448.4 linkuse as main transcriptc.579-962C>T intron_variant 3
SRSF4ENST00000634348.1 linkuse as main transcriptn.6669C>T non_coding_transcript_exon_variant 6/75
SRSF4ENST00000691479.1 linkuse as main transcriptc.*790C>T 3_prime_UTR_variant, NMD_transcript_variant 9/10

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152064
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251418
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000472
AC:
69
AN:
1461464
Hom.:
0
Cov.:
30
AF XY:
0.0000440
AC XY:
32
AN XY:
727050
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:
0.0000576
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152064
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74286
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2

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 GeneticsJul 25, 2023The c.583C>T (p.R195C) alteration is located in exon 5 (coding exon 5) of the SRSF4 gene. This alteration results from a C to T substitution at nucleotide position 583, causing the arginine (R) at amino acid position 195 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
0.44
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.031
D
MetaRNN
Uncertain
0.58
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-6.3
D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.57
MVP
0.32
MPC
0.74
ClinPred
0.98
D
GERP RS
5.4
Varity_R
0.60
gMVP
0.65

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: rs139367933; hg19: chr1-29476700; COSMIC: COSV65694283; COSMIC: COSV65694283; API