15-101275344-T-C

Position:

• chr15-101275344-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018445.6(SELENOS):​c.229A>G​(p.Lys77Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000621 in 1,577,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: SELENOS NM_018445.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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]

SELENOS (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059395224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENOS	NM_018445.6	c.229A>G	p.Lys77Glu	missense_variant	3/6	ENST00000526049.6	NP_060915.2
SELENOS	NM_203472.3	c.229A>G	p.Lys77Glu	missense_variant	3/7		NP_982298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENOS	ENST00000526049.6	c.229A>G	p.Lys77Glu	missense_variant	3/6	1	NM_018445.6	ENSP00000433541.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000170 AC: 33 AN: 193852 Hom.: 0 AF XY: 0.000173 AC XY: 18 AN XY: 103806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000599

Gnomad ASJ exome AF: 0.00122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.000589

GnomAD4 exome AF: 0.0000575 AC: 82 AN: 1424974 Hom.: 0 Cov.: 30 AF XY: 0.0000567 AC XY: 40 AN XY: 705462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000525

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.0000508

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74498

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000585 AC: 7

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

Feb 28, 2024

The c.229A>G (p.K77E) alteration is located in exon 3 (coding exon 3) of the VIMP gene. This alteration results from a A to G substitution at nucleotide position 229, causing the lysine (K) at amino acid position 77 to be replaced by a glutamic acid (E). 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	-0.26	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T;.;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	.;.;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.059	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.23	T;T;T;T
Sift4G	Uncertain	0.043	D;D;D;.
Polyphen		0.72	P;.;P;.
Vest4		0.28
MutPred		0.57		Loss of methylation at K77 (P = 0.006);.;Loss of methylation at K77 (P = 0.006);.;
MVP		0.20
MPC		0.20
ClinPred		0.15	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56

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

LitVar

Other links and lift over

dbSNP: rs199744629; hg19: chr15-101815549;