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GeneBe

1-29148709-T-C

Variant summary

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

The NM_005626.5(SRSF4):c.1186A>G(p.Lys396Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000271 in 1,583,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SRSF4
NM_005626.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.29
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 Benign. Variant got -7 ACMG points.

PP2
Missense variant where missense usually causes diseases, SRSF4
BP4
Computational evidence support a benign effect (MetaRNN=0.03361252).
BS2
High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRSF4NM_005626.5 linkuse as main transcriptc.1186A>G p.Lys396Glu missense_variant 6/6 ENST00000373795.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRSF4ENST00000373795.7 linkuse as main transcriptc.1186A>G p.Lys396Glu missense_variant 6/61 NM_005626.5 P1
SRSF4ENST00000466448.4 linkuse as main transcriptc.1096A>G p.Lys366Glu missense_variant 5/53
SRSF4ENST00000634348.1 linkuse as main transcriptn.7272A>G non_coding_transcript_exon_variant 7/75
SRSF4ENST00000691479.1 linkuse as main transcriptc.*1393A>G 3_prime_UTR_variant, NMD_transcript_variant 10/10

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151622
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
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:
0.0000452
AC:
11
AN:
243390
Hom.:
0
AF XY:
0.0000304
AC XY:
4
AN XY:
131770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000619
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:
0.0000286
AC:
41
AN:
1432174
Hom.:
0
Cov.:
29
AF XY:
0.0000295
AC XY:
21
AN XY:
712014
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000619
Gnomad4 SAS exome
AF:
0.0000242
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000119
Gnomad4 OTH exome
AF:
0.0000339
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151738
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74160
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000664
AC:
8

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 GeneticsMay 24, 2023The c.1186A>G (p.K396E) alteration is located in exon 6 (coding exon 6) of the SRSF4 gene. This alteration results from a A to G substitution at nucleotide position 1186, causing the lysine (K) at amino acid position 396 to be replaced by a glutamic acid (E). 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
0.094
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.018
T;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.53
T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.034
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.14
N;.
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.10
N;.
REVEL
Benign
0.037
Sift
Uncertain
0.0030
D;.
Sift4G
Uncertain
0.060
T;T
Polyphen
0.90
P;.
Vest4
0.24
MVP
0.17
MPC
0.31
ClinPred
0.19
T
GERP RS
5.0
Varity_R
0.16
gMVP
0.38

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: rs138237342; hg19: chr1-29475221; API