15-101274666-T-A

Variant names:

• chr15-101274666-T-A
• NM_018445.6:c.334A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018445.6(SELENOS):​c.334A>T​(p.Arg112Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SELENOS NM_018445.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENOS	NM_018445.6	c.334A>T	p.Arg112Trp	missense_variant	Exon 4 of 6	ENST00000526049.6	NP_060915.2
SELENOS	NM_203472.3	c.334A>T	p.Arg112Trp	missense_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.334A>T	p.Arg112Trp	missense_variant	Exon 4 of 6	1	NM_018445.6	ENSP00000433541.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458956 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725684

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.334A>T (p.R112W) alteration is located in exon 4 (coding exon 4) of the VIMP gene. This alteration results from a A to T substitution at nucleotide position 334, causing the arginine (R) at amino acid position 112 to be replaced by a tryptophan (W). 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	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.3	M;.;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.3	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;.
Polyphen		1.0	D;.;D;.
Vest4		0.81
MutPred		0.63		Loss of methylation at K115 (P = 0.0552);.;Loss of methylation at K115 (P = 0.0552);.;
MVP		0.33
MPC		0.24
ClinPred		0.98	D
GERP RS		1.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.87

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: chr15-101814871;