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GeneBe

15-101274645-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018445.6(SELENOS):c.355T>C(p.Trp119Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SELENOS
NM_018445.6 missense

Scores

5
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.59
Variant links:
Genes affected
SELENOS (HGNC:30396): (selenoprotein S) This gene encodes a transmembrane protein that is localized in the endoplasmic reticulum (ER). It is involved in the degradation process of misfolded proteins in the ER, and may also have a role in inflammation control. This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Two additional phylogenetically conserved stem-loop structures (Stem-loop 1 and Stem-loop 2) in the 3' UTR of this mRNA have been shown to function as modulators of Sec insertion. An alternatively spliced transcript variant, lacking the SECIS element and encoding a non-Sec containing shorter isoform, has been described for this gene (PMID:23614019). [provided by RefSeq, Jul 2017]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SELENOSNM_018445.6 linkuse as main transcriptc.355T>C p.Trp119Arg missense_variant 4/6 ENST00000526049.6
SELENOSNM_203472.3 linkuse as main transcriptc.355T>C p.Trp119Arg missense_variant 4/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SELENOSENST00000526049.6 linkuse as main transcriptc.355T>C p.Trp119Arg missense_variant 4/61 NM_018445.6 P1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000524
AC:
13
AN:
248300
Hom.:
0
AF XY:
0.0000371
AC XY:
5
AN XY:
134768
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000146
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:
0.0000622
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461170
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
726862
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
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:
0.0000225
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.0000459
AC:
7
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000122
AC:
1
ExAC
AF:
0.0000414
AC:
5

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 GeneticsOct 25, 2022The c.355T>C (p.W119R) alteration is located in exon 4 (coding exon 4) of the VIMP gene. This alteration results from a T to C substitution at nucleotide position 355, causing the tryptophan (W) at amino acid position 119 to be replaced by an arginine (R). 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
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.14
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Benign
0.35
T;.;T;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Benign
0.016
T
MetaRNN
Pathogenic
0.79
D;D;D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Pathogenic
3.1
M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-9.7
D;D;D;D
REVEL
Uncertain
0.49
Sift
Uncertain
0.0060
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
0.96
D;.;D;.
Vest4
0.86
MutPred
0.67
Loss of catalytic residue at M122 (P = 0.0199);.;Loss of catalytic residue at M122 (P = 0.0199);.;
MVP
0.40
MPC
0.29
ClinPred
0.88
D
GERP RS
4.4
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.75

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: rs367550223; hg19: chr15-101814850; API