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GeneBe

1-29148594-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_005626.5(SRSF4):c.1301C>T(p.Ala434Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SRSF4
NM_005626.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.688
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2
Missense variant where missense usually causes diseases, SRSF4
BP4
Computational evidence support a benign effect (MetaRNN=0.02947402).
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRSF4NM_005626.5 linkuse as main transcriptc.1301C>T p.Ala434Val missense_variant 6/6 ENST00000373795.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRSF4ENST00000373795.7 linkuse as main transcriptc.1301C>T p.Ala434Val missense_variant 6/61 NM_005626.5 P1
SRSF4ENST00000634348.1 linkuse as main transcriptn.7387C>T non_coding_transcript_exon_variant 7/75
SRSF4ENST00000691479.1 linkuse as main transcriptc.*1508C>T 3_prime_UTR_variant, NMD_transcript_variant 10/10

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000771
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251388
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000381
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461800
Hom.:
0
Cov.:
29
AF XY:
0.00000688
AC XY:
5
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000176
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3

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 GeneticsDec 16, 2023The c.1301C>T (p.A434V) alteration is located in exon 6 (coding exon 6) of the SRSF4 gene. This alteration results from a C to T substitution at nucleotide position 1301, causing the alanine (A) at amino acid position 434 to be replaced by a valine (V). 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
Benign
0.076
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0060
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.66
T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.029
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.16
N
REVEL
Benign
0.043
Sift
Uncertain
0.0080
D
Sift4G
Benign
0.45
T
Polyphen
0.10
B
Vest4
0.051
MutPred
0.27
Loss of relative solvent accessibility (P = 0.0404);
MVP
0.11
MPC
0.22
ClinPred
0.094
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.062
gMVP
0.39

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: rs774641267; hg19: chr1-29475106; API