15-101276625-G-C

Variant names:

• chr15-101276625-G-C
• NM_018445.6:c.127C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018445.6(SELENOS):​c.127C>G​(p.Leu43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L43F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SELENOS NM_018445.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10874736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENOS	NM_018445.6	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 6	ENST00000526049.6	NP_060915.2
SELENOS	NM_203472.3	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 7		NP_982298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENOS	ENST00000526049.6	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 6	1	NM_018445.6	ENSP00000433541.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461524 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.017	T;.;T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.62	.;.;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.48	N;.;N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.65	N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.86	T;T;T;T
Sift4G	Benign	0.95	T;T;T;.
Polyphen		0.0030	B;.;B;.
Vest4		0.29
MutPred		0.65		Gain of catalytic residue at L43 (P = 0.0208);.;Gain of catalytic residue at L43 (P = 0.0208);.;
MVP		0.092
MPC		0.038
ClinPred		0.039	T
GERP RS		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-101816830;