chr5-66170712-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001077199.3(SREK1):​c.1249C>T​(p.Arg417Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,601,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R417Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SREK1
NM_001077199.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0270
Variant links:
Genes affected
SREK1 (HGNC:17882): (splicing regulatory glutamic acid and lysine rich protein 1) This gene encodes a member of a family of serine/arginine-rich (SR) splicing proteins containing RNA recognition motif (RRM) domains. The encoded protein interacts with other SR proteins to modulate splice site selection. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07219979).
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SREK1NM_001077199.3 linkc.1249C>T p.Arg417Trp missense_variant Exon 9 of 12 ENST00000334121.11 NP_001070667.1 Q8WXA9-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SREK1ENST00000334121.11 linkc.1249C>T p.Arg417Trp missense_variant Exon 9 of 12 2 NM_001077199.3 ENSP00000334538.6 Q8WXA9-2

Frequencies

GnomAD3 genomes
AF:
0.0000134
AC:
2
AN:
149014
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000672
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000196
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:
0.00000437
AC:
1
AN:
228846
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
123486
show subpopulations
Gnomad AFR exome
AF:
0.0000666
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000482
AC:
7
AN:
1452754
Hom.:
0
Cov.:
31
AF XY:
0.00000416
AC XY:
3
AN XY:
721900
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000452
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000134
AC:
2
AN:
149014
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
1
AN XY:
72526
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000672
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000196
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1249C>T (p.R417W) alteration is located in exon 9 (coding exon 9) of the SREK1 gene. This alteration results from a C to T substitution at nucleotide position 1249, causing the arginine (R) at amino acid position 417 to be replaced by a tryptophan (W). 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
0.24
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.81
T;T
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.072
T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
1.8
.;L
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Benign
0.20
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
0.0070
B;D
Vest4
0.39
MutPred
0.24
.;Gain of ubiquitination at K297 (P = 0.0737);
MVP
0.45
MPC
0.30
ClinPred
0.91
D
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.045

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: rs1313616004; hg19: chr5-65466540; API