15-101275264-T-C

Variant names:

• chr15-101275264-T-C
• rs371871361
• NM_018445.6:c.309A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_018445.6(SELENOS):​c.309A>G​(p.Lys103Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SELENOS NM_018445.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.413
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=-0.413 with no splicing effect.

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.309A>G	p.Lys103Lys	synonymous	Exon 3 of 6	NP_060915.2
	SELENOS	NM_203472.3		c.309A>G	p.Lys103Lys	synonymous	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.309A>G	p.Lys103Lys	synonymous	Exon 3 of 6	ENSP00000433541.1	Q9BQE4
	SELENOS	ENST00000398226.8	TSL:1	c.309A>G	p.Lys103Lys	synonymous	Exon 3 of 7	ENSP00000381282.3	Q9BQE4
	SELENOS	ENST00000528346.1	TSL:3	c.429A>G	p.Lys143Lys	synonymous	Exon 3 of 6	ENSP00000434842.1	E9PN30

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402660 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 692528

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31860

American (AMR) AF: 0.00 AC: 0 AN: 34090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25152

East Asian (EAS) AF: 0.00 AC: 0 AN: 37872

South Asian (SAS) AF: 0.00 AC: 0 AN: 77738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081954

Other (OTH) AF: 0.0000172 AC: 1 AN: 58138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.51
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs371871361; hg19: chr15-101815469;