Genetic Variant NM_018445.6:c.-105G>A (chr15-101277522-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018445.6(SELENOS):c.-105G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,292,772 control chromosomes in the GnomAD database, including 19,756 homozygotes. 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: 𝑓 0.24 ( 6415 hom., cov: 32)

Exomes 𝑓: 0.14 ( 13341 hom. )

Consequence

SELENOS
NM_018445.6 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.134

Publications

51 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENOS	NM_018445.6 link	c.-105G>A		upstream_gene_variant		ENST00000526049.6	NP_060915.2
SELENOS	NM_203472.3 link	c.-105G>A		upstream_gene_variant			NP_982298.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENOS	ENST00000526049.6 link	c.-105G>A		upstream_gene_variant		1	NM_018445.6	ENSP00000433541.1		Q9BQE4

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35853

AN:

151952

Hom.:

6400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.500

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.0808

Gnomad SAS

AF:

0.0600

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.207

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.218

GnomAD4 exome

AF:

0.141

AC:

160830

AN:

1140710

Hom.:

13341

Cov.:

AF XY:

0.139

AC XY:

76281

AN XY:

548070

show subpopulations

African (AFR)

AF:

0.513

AC:

11682

AN:

22766

American (AMR)

AF:

0.193

AC:

1574

AN:

8172

Ashkenazi Jewish (ASJ)

AF:

0.132

AC:

1963

AN:

14832

East Asian (EAS)

AF:

0.0593

AC:

1516

AN:

25558

South Asian (SAS)

AF:

0.0682

AC:

2397

AN:

35170

European-Finnish (FIN)

AF:

0.153

AC:

3913

AN:

25598

Middle Eastern (MID)

AF:

0.134

AC:

419

AN:

3134

European-Non Finnish (NFE)

AF:

0.136

AC:

130210

AN:

959058

Other (OTH)

AF:

0.154

AC:

7156

AN:

46422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

6999

13998

20996

27995

34994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5244

10488

15732

20976

26220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.236

AC:

35910

AN:

152062

Hom.:

6415

Cov.:

AF XY:

0.231

AC XY:

17202

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.500

AC:

20751

AN:

41498

American (AMR)

AF:

0.187

AC:

2853

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

456

AN:

3472

East Asian (EAS)

AF:

0.0802

AC:

415

AN:

5172

South Asian (SAS)

AF:

0.0600

AC:

290

AN:

4830

European-Finnish (FIN)

AF:

0.149

AC:

1579

AN:

10570

Middle Eastern (MID)

AF:

0.212

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.133

AC:

9034

AN:

67934

Other (OTH)

AF:

0.222

AC:

468

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1249

2499

3748

4998

6247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.182

Hom.:

454

Bravo

AF:

0.254

Asia WGS

AF:

0.104

AC:

360

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.8

(source)

DANN

Benign

0.92

PhyloP100

-0.13

PromoterAI

-0.034

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over