15-101275350-C-A

Variant names:

• chr15-101275350-C-A
• rs1371721068
• NM_018445.6:c.223G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018445.6(SELENOS):​c.223G>T​(p.Val75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V75I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SELENOS NM_018445.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018445.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENOS	NM_018445.6	MANE Select	c.223G>T	p.Val75Phe	missense	Exon 3 of 6	NP_060915.2
	SELENOS	NM_203472.3		c.223G>T	p.Val75Phe	missense	Exon 3 of 7	NP_982298.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENOS	ENST00000526049.6	TSL:1 MANE Select	c.223G>T	p.Val75Phe	missense	Exon 3 of 6	ENSP00000433541.1	Q9BQE4
	SELENOS	ENST00000398226.8	TSL:1	c.223G>T	p.Val75Phe	missense	Exon 3 of 7	ENSP00000381282.3	Q9BQE4
	SELENOS	ENST00000528346.1	TSL:3	c.343G>T	p.Val115Phe	missense	Exon 3 of 6	ENSP00000434842.1	E9PN30

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420074 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702786

African (AFR) AF: 0.0000307 AC: 1 AN: 32618

American (AMR) AF: 0.00 AC: 0 AN: 36986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25378

East Asian (EAS) AF: 0.00 AC: 0 AN: 38728

South Asian (SAS) AF: 0.00 AC: 0 AN: 80180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090406

Other (OTH) AF: 0.00 AC: 0 AN: 58790

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Benign	0.073	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.92	P
Vest4		0.71
MutPred		0.71		Loss of MoRF binding (P = 0.0927)
MVP		0.28
MPC		0.25
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.54
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs1371721068; hg19: chr15-101815555;