15-101276643-T-C

Variant summary

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

The NM_018445.6(SELENOS):c.109A>G(p.Ile37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,613,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: SELENOS NM_018445.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.306

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=0.08218306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENOS	NM_018445.6	c.109A>G	p.Ile37Val	missense_variant	2/6	ENST00000526049.6
SELENOS	NM_203472.3	c.109A>G	p.Ile37Val	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENOS	ENST00000526049.6	c.109A>G	p.Ile37Val	missense_variant	2/6	1	NM_018445.6	P1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000471 AC: 117 AN: 248458 Hom.: 0 AF XY: 0.000438 AC XY: 59 AN XY: 134850

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000914

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000716 AC: 1046 AN: 1461058 Hom.: 0 Cov.: 31 AF XY: 0.000684 AC XY: 497 AN XY: 726804

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000860

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152074 Hom.: 0 Cov.: 31 AF XY: 0.000458 AC XY: 34 AN XY: 74272

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000756 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000722 AC: 6

ExAC AF: 0.000513 AC: 62

EpiCase AF: 0.000709

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.109A>G (p.I37V) alteration is located in exon 2 (coding exon 2) of the VIMP gene. This alteration results from a A to G substitution at nucleotide position 109, causing the isoleucine (I) at amino acid position 37 to be replaced by a valine (V). 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	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	15
Dann	Benign	0.75
DEOGEN2	Benign	0.024	T;.;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L;.
MutationTaster	Benign	0.81	N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.44	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.16	T;T;T;.
Polyphen		0.14	B;.;B;.
Vest4		0.32
MVP		0.15
MPC		0.043
ClinPred		0.011	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs200543084; hg19: chr15-101816848;