NM_018445.6:c.319C>T

Variant names:

• chr15-101274681-G-A
• rs889578831
• NM_018445.6:c.319C>T

Variant summary

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

The NM_018445.6(SELENOS):​c.319C>T​(p.Leu107Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SELENOS NM_018445.6 missense, splice_region
• Scores: Splicing: ADA: 0.9954
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENOS	NM_018445.6	c.319C>T	p.Leu107Phe	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000526049.6	NP_060915.2
SELENOS	NM_203472.3	c.319C>T	p.Leu107Phe	missense_variant, splice_region_variant	Exon 4 of 7		NP_982298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENOS	ENST00000526049.6	c.319C>T	p.Leu107Phe	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_018445.6	ENSP00000433541.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.319C>T (p.L107F) alteration is located in exon 4 (coding exon 4) of the VIMP gene. This alteration results from a C to T substitution at nucleotide position 319, causing the leucine (L) at amino acid position 107 to be replaced by a phenylalanine (F). 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	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.0	M;.;M;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Benign	0.077	T;T;T;.
Polyphen		1.0	D;.;D;.
Vest4		0.38
MutPred		0.62		Gain of methylation at K111 (P = 0.0858);.;Gain of methylation at K111 (P = 0.0858);.;
MVP		0.29
MPC		0.24
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
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

Other links and lift over

dbSNP: rs889578831; hg19: chr15-101814886;