dbSNP rs368229041: SELENOS:p.Pro165Leu (chr15-101272847-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

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

The NM_018445.6(SELENOS):c.494C>T(p.Pro165Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,606,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SELENOS
NM_018445.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.81

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]

SELENOS links:

Genome browser will be placed here

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, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENOS	NM_018445.6 link	c.494C>T	p.Pro165Leu	missense_variant	Exon 6 of 6	ENST00000526049.6	NP_060915.2
SELENOS	NM_203472.3 link	c.494C>T	p.Pro165Leu	missense_variant	Exon 6 of 7		NP_982298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENOS	ENST00000526049.6 link	c.494C>T	p.Pro165Leu	missense_variant	Exon 6 of 6	1	NM_018445.6	ENSP00000433541.1		Q9BQE4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000423

AC:

AN:

236298

Hom.:

AF XY:

0.00000781

AC XY:

AN XY:

128012

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:

0.0000350

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1454880

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000229

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:

0.00000361

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

.;.;D;D

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Pathogenic

3.4

M;.;M;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-8.5

D;D;D;D

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

0.83

P;.;P;.

Vest4

0.82

MutPred

0.58

Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);.;

MVP

0.36

MPC

0.24

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.78

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over